Textbook of Psychiatry/Mood Disorders

Introduction

Manic-depressive illness is known since the era of Hippocrates (460–357 BC), Galen (131–201 AD) and Areteus from Kappadokia, and is described in ancient medical texts. Some authors believe that King Saul was also suffering from this disease and David used to relieve his depression by playing music for him. The ancient Greeks and Romans coined the terms "melancholia" and "mania." Hippocrates was the first to describe melancholia which is the Greek word for "black bile" and simultaneously postulated a biochemical origin according to the scientific frame of that era, linking it to Saturn and the autumn.

Mania was described as madness with elevated mood but it included a broad spectrum of excited psychotic states the way we understand them today. Soranus was the first to describe mixed states. Aretaeus of Cappadocia (2nd century AD) is considered to be the one who strongly connected melancholia with mania and made a description of manic episodes very close to the modern approach, including psychotic features and seasonality.

Another interesting element in the theories that emerged during antiquity was the concept of temperament which was originally based on harmony and balance of the four humors, of which the sanguine humor was considered to be the healthiest but also predisposing to mania. The melancholic temperament was linked to black bile and was considered to predispose to melancholia. Since the time of Aristotle (384–322 BC), the melancholic temperament was linked to creativity.

During the 10th and 11th century AD the Arab scholars dominated (Ishaq Ibn Imran, Avicenna and others). In 1621 Robert Burton wrote the first English-speaking text on the field of mood disorders "The Anatomy of Melancholy." Later, the works of Jean-Philippe Esquirol (1772-1840), Benjamin Rush (1745–1813), Henry Maudsley (1835–1918), Jean-Pierre Falret (1794-1870) and Jules Gabriel Francois Baillarger (1809-1890) established the connection between depression and mania. Finally, Emil Kraepelin (1856–1926) established manic-depressive illness as a nosological entity (and separated it from schizophrenia) on the basis of heredity, longitudinal follow-up and a supposed favorable outcome.

Recent research data has reshaped our definition and understanding of bipolar and other mood disorders. Today the suboptimal outcome of mood disorders is well documented, especially in relationship to younger age of onset and to alcohol and substance abuse. Suicide is another major concern since up to 75% of patients who commit suicide suffer from some type of mood disorder.

Recently the World Health Organization (WHO) has ranked neuropsychiatric disorders as one of the most disability inducing causes world-wide, more disabling than cancer and cardiovascular diseases, and equal to injuries from all causes (World Health Organization, 2003). Affective disorders combined are the most disabling neuropsychiatric conditions and one of the 4 leading disability causes.

Phenomenology

Epidemiology

DSM-IV-TR unipolar major depressive disorder (U-MDD) is reported to be the most common mood disorder (Weissman et al. 1996). The overall current prevalence of MDD is estimated to be 4.7% for males and 6% for females and the annual incidence is around 1.59%. Depression of any type may afflict 10-25% of females and 5-12% of males at some time during their lives with the rates varying widely and depending on ethnic background, type of residential area, gender, age, social support and general somatic health status. The results of the US Epidemiologic Catchment Area (ECA) study suggest that disabling mood disorders affect as high as 5-8% of the general population and that if milder depression is included then the lifetime prevalence increases to 17% (National Comorbidity Study -NCS). When subclinical mood states are included, it is reported that one third of the general population will be affected (Dryman & Eaton, 1991; Eaton, Dryman, Sorenson, & McCutcheon, 1989; Eaton, Kramer et al. 1989). In spite of treatment, disability rates are high and suicide occurs in about 15% of patients, especially in men. Conversely, a significant proportion of suicide victims suffer from some kind of depressive state (Parkar, Dawani, & Weiss, 2006; Seguin et al. 2006; Zonda, 2006). For some people depression is a single episode in life but around half of those experiencing an episode will experience more in the future, and the likelihood after the second episode is to experience a third episode within a decade or so. One third of patients will recover within the first 2-3 months, another third will need 6-8 months and around 15% of patients will not have recovered after 2 years, and they are likely to develop a chronic course (Kruijshaar et al. 2005; Patten & Lee, 2004, 2005; Patten, 2006; Patten et al. 2006; Patten, 2007; Waraich, Goldner, Somers, & Hsu, 2004; Wulsin, Vaillant, & Wells, 1999).

The epidemiological data concerning the risk factors for MDD is rich but inconclusive. Women are twice as likely as men to experience an episode of MDD (Coryell, Endicott, Andreasen, & Keller, 1985; Kessler, McGonagle, Swartz, Blazer, & Nelson, 1993; Tennant, 1985; Weissman et al. 1988) and age plays a complex role (Koeniq, Meador, Cotlen, & Blazer, 1988). MDD has an average age of onset between 20 and 40 years while bipolar disorder may appear more frequently in the early 20s (Weissman et al. 1988). The effect of socioeconomic status is weak if it exists at all (Hollingshead & Redlich, 2007). Marital status appears to be one of the most consistent risk factors for MDD with recently widowed, separated and divorced persons being at higher risk, and single and married persons at lower risk. A family history of MDD, especially in first-degree relatives, constitutes a major risk factor along with family history of suicide and alcoholism. Early childhood abuse per se may be related to increased neuroendocrine stress reactivity, which is further enhanced when additional trauma is experienced in adulthood (Heim et al. 2002). Some personality features (introversion, worry, dependency and interpersonal sensitivity) as well as social stressors and social support also constitute risk factors (Farmer et al. 2001; Iacovides, Fountoulakis, Fotiou, & Kaprinis, 2002; Paykel, 1994, 2001a, 2001b). Life events (especially loss and bereavement), chronic stress (financial, family and interpersonal difficulties), and daily hassles as well as routine changes even due to positive events (e.g., change in residency due to promotion at work) all constitute risk factors (Fotiou, Fountoulakis, Iacovides, & Kaprinis, 2003; Rijsdijk et al.2001). In addition, it has been reported that adolescent life events predicted an increased risk for major depression diagnosis in early adulthood (Pine, Cohen, Johnson, & Brook, 2002) The conclusion from few available community-based studies suggested that younger age, low social class, negative and stressful life events linked to the family were associated with increased risk of new onset depression (Friis, Wittchen, Pfister, & Lieb, 2002).

Originally it has been suggested that the classic manic depressive psychosis had a prevalence of around 1% (0.4-1.6%). However, today we know that the true prevalence depends on the definition, and to an extent, the sub-threshold bipolar cases and pseudo-unipolar patients. In addition, personality disorders (PDs), especially borderline personality disorder, are included under the umbrella of the bipolar spectrum or under unipolar depression. Another open question is whether the avoidant and the dependent PDs constitute real PDs or instead are residuals of a previously experienced major depressive episode. This is because these two PDs have been detected only in patient populations and not really in general population samples.

DSM-IV-TR Bipolar disorder (BD) type I and type II have a combined prevalence rate of up to 3.7%. The literature on the lifetime prevalence of BD suggests an overall rate of 3-6.5% including a wider spectrum of bipolarity in comparison to the DSM-IV-TR definition (Acorn, 1993; Angst, 1998; Judd & Akiskal, 2003).

As for other risk factors (Laursen, Munk-Olsen, Nordentoft, & Bo Mortensen, 2007), although younger age, marital status (separated/divorced) and negative life events have been suggested to play a role, perhaps the best proven risk factor is the genetic transmission of bipolar disorder, which is much higher than that of MDD.

Clinical symptoms and classification

The onset of mood episodes can be acute or insidious, and emerge from a low-grade, intermittent, and protracted mood substrate which can resemble a dysthymic or cyclothymic state or even personality features (Fogel, Eaton, & Ford, 2006). These mood states can also prevail during the inter-episode period and may give rise to low quality of life, interpersonal conflicts and significant global disability. Furthermore, these subthreshold disorders are quite frequent in the families of patients (Shankman, Klein, Lewinsohn, Seeley, & Small, 2008). Dysthymic and cyclothymic disorders are recognized by contemporary classification systems as separate diagnostic entities and often do not lead to the manifestation of a full blown mood episode. Dysthymic disorder corresponds largely to a chronic mild form of depression with a relatively stable social functioning.

Bipolar disorders (previously called manic-depressive psychosis) consists of at least one hypomanic, manic, or mixed episode. Mixed episodes represent a simultaneous mixture of depressive and manic or hypomanic manifestations. Although a minority of patients experience only manic episodes, most bipolar disorder (BD) patients experience episodes of both polarity.

The classical definition of BD suggests that this disorder is characterized by the presence and alteration of manic and depressive episodes with a return to premorbid level of functioning between the episodes and a favorable outcome in comparison to schizophrenia (Kraepelin, 1921). Today we know that this is not always the case (Tohen, Waternaux, & Tsuang, 1990). The Kraepelinian concept largely corresponds to BD type I (BD-I) according to DSM-IV-TR (American Psychiatric Association, 2000). Typically, BD-I starts before the age of 40. Frequently the correct diagnosis is made after several years because the first episode is psychotic-like or depressive and the diagnosis is only evident after a manic or mixed episode emerges. Another type, BD-II is officially recognized as a bipolar illness subtype and it is characterized by the presence of hypomanic instead of manic episodes. However, it is important to note that according to DSM-IV-TR (American Psychiatric Association, 2000) hypomania is defined mainly in terms of a shorter duration of the episode. BD-II is more prevalent than BD-I disorder. An additional complicating factor for diagnosis is that patients usually experience hypomania as a recovery from depression and almost always as a pleasant ego-syntonic mood state.

Depressive episodes are considered to be the second diagnostic pillar of BD. However, in contrast to manic episodes which lead to the diagnosis of BD immediately, depressive episodes pose a dilemma to the clinician regarding whether or not he or she faces a unipolar depression or a BD. This is an important dilemma to solve since the treatment of these disorders differ. However, it has been estimated that more than half of patients originally manifesting a depressive episode will turn out to have BD in the next 20 years (Angst, Sellaro, Stassen, & Gamma, 2005). Unipolar-depressed patients who later "convert" to BD over time, as well as patients with bipolar depression manifest more frequently "atypical" features of depression (hypersomnia, hyperphagia, leaden paralysis, long term interpersonal rejection sensitivity, psychomotor retardation, psychotic features, pathological guilt and mood lability)(Perugi et al. 1998). BD patients also tend to have earlier age of onset, more prior episodes of depression, shorter depressive episodes, and family history of BD (Akiskal & Benazzi, 2008; Mitchell, Goodwin, Johnson, & Hirschfeld, 2008). Family history of BD is a strong predictor of bipolarity even in children and adolescents (Geller, Fox, & Clark, 1994). DSM-IV-TR recognizes atypical features of depression (Davidson, Miller, Turnbull, & Sullivan, 1982; Fountoulakis, Iacovides, Nimatoudis, Kaprinis, & Ierodiakonou, 1999; Thase, 2007). This depressive subtype includes the presence of personality-like features such as long-term interpersonal rejection sensitivity, and somatic symptoms such as reverse vegetative signs, hypersomnia, increased appetite, weight gain and leaden paralysis. There is strong evidence linking atypical depression to BD-II (Akiskal & Benazzi, 2005).

Mixed episodes are also considered to be part of the BD picture, and according to DSM-IV-TR are defined as the co-existence of both depressive and manic symptoms to the extent that the criteria for both a manic and a depressed episode are fulfilled (Akiskal & Benazzi, 2004). Alterations in mood characterize several other DSM disorders which have a bipolar character. These include cyclothymic disorder and borderline personality disorder. However, there is a constellation of types of affective episodes which are not part of the official classification and they are so prevalent in real life clinical practice that many authors consider them to be the rule rather than the exception.

Sometimes there is a mixture of manic and depressive symptoms in a combination which does not fulfill the specific DSM criteria for a manic, depressive or mixed episode. Therefore, the only possible diagnosis is that of a Not-Otherwise-Specified (NOS) mood episode (Akiskal, 1996; Akiskal et al. 1998).

Often manic symptoms can go unnoticed by the clinician because instead of being hyperthymic, the mood is irritable and is diluted in the presence of depressed thought content and suicidal ideation. Such a presentation may lead the clinician to the diagnosis of anxious or agitated depression, or worse, of a personality disorder, instead of a mixed or mixed-NOS mood episode. Frequently, this irritable mood can result in aggressive behavior especially if confronted or rejected while having grandiose or paranoid delusions. These patients may be the most aggressive seen in the emergency room (Maj, Pirozzi, Magliano, & Bartoli, 2003; Sato, Bottlender, Kleindienst, & Moller, 2005).

There is evidence that an excited/irritable state can develop when antidepressants, especially dual action ones, are used. Many patients will not develop a classic manic episode in response; many will either develop a full blown mixed episode or more likely a DSM sub-threshold mixed-NOS episode with the presence of a small number of manic symptoms in combination with depression, especially agitation, and this state may persist and worsen if more aggressive antidepressant treatment is tried.

Rapid cycling refers to patients suffering from at least 4 mood episodes in a year. It seems that females are more often rapid-cyclers as well as higher social class subjects. In essence, these patients tend to be symptomatic most of their life and are considered to be refractory to lithium. The diagnosis may elude for prolonged periods of time and the patients can receive the diagnosis of a personality disorder or cyclothymia. Treatment of rapid cycling is based on a complex, delicate and difficult to design multiple pharmacotherapy which includes atypical antipsychotics, anticonvulsants and even antidepressants, although the latter are believed to induce rapid cycling (Bauer et al. 1994).

Psychotic features are common in bipolar patients and may include delusions or hallucinations of any type. They can either be mood congruent or mood incongruent. In order to make the diagnosis of schizoaffective disorder according to DSM-IV-TR there must be a psychotic episode in the absence of prominent mood symptoms. However, according to ICD-10 this diagnostic boundary is vague and differential classification is often difficult.

Alcohol and substance abuse are very common problems in BD. Drug abuse may precipitate an earlier onset of BD-I in those who already have a familial predisposition for mania. Alcohol abuse may be present in more than half of patients. It seems that frequently this represents self-medication efforts and abuse is particularly problematic during adolescence and early adulthood. At this age period substance and alcohol abuse may not only suppress symptoms but also enhance specific desired activities (e.g., high school performance, sex etc.). Alcohol abuse can cause further disinhibition and may cause the patient to manifest physical aggression especially towards the family, with "crimes of passion" being the most tragic result. BD patients tend to abuse stimulant drugs. Familial diathesis for mania is significantly associated with the abuse of alcohol and drugs and it is possible that there is a common familial-genetic diathesis for a subtype of BD-I, alcohol and stimulant abuse (Winokur et al.1998).

The cognitive deficits of BD patients have not been studied adequately. However, in contrast to the early Kraepelinian concept for a favorable functioning outcome, recent studies suggest there is a significant degree of psychosocial impairment even when patients are euthymic and report that only a minority achieves complete functional recovery (Daban et al. 2006; Goldberg, Harrow, & Grossman, 1995a, 1995b; Keck et al. 1998; Martinez-Aran et al. 2007; Mur, Portella, Martinez-Aran, Pifarre, & Vieta, 2007; Strakowski et al. 1998). Cognitive impairment is reported to exist in both BD-I and BD-II patients, although more so in the BD-I group and this is true even during the euthymic period. The cognitive deficit can be worse during the manic phase but it is present during all phases of the illness (Dixon, Kravariti, Frith, Murray, & McGuire, 2004; Malhi, Ivanovski, Szekeres, & Olley, 2004). However, when compared to patients with schizophrenia, BD patients demonstrate a lesser degree of deficits, particularly concerning premorbid and current intelligence quotient and perhaps attention, verbal memory,verbal fluency and executive functions (Mur et al. 2007; Torrent et al. 2006). The pattern of the neurocognitive deficit implicates the prefrontal cortex and temporo-limbic structures, especially ventromedial areas as well as the amygdala and the hippocampus.

Mood disorders are characterized by a constellation of symptoms and signs. The terms "depressed mood," "anhedonia" and "elevated mood" are central to the definition and diagnosis of these disorders.

Mood

• Euthymia refers to the normal range of mood, and the absence of any disorder.

• Mourning refers to the experience of sadness as a consequence of a loss of a loved one. It includes, crying, sadness, preoccupation with the lost person and related memories.

• Depressed mood means that the patient experiences a "negative" and unpleasant affect, and in English and other western cultures and languages the words (or their linguistic equivalents) "depressed," "anguished," "mournful," "sad," "anxious," "blues" are used. The word "depressed" is increasingly used because of the higher information (partially because of the internet) the public has today on depression. The way patient uses describes this experience depends on his/her cultural and educational background, and can focus on bodily function or on existential and interpersonal dysphoria and difficulties. Somatic complaints are more prominent in milder cases usually seen in the primary care setting, particularly in patients with anxious depression. These patients were considered to suffer from "masked" depression.

• Anhedonia refers to the inability to experience normal emotions. Frequently, patients with anhedonia are incapable of even feeling the depressed affect and they can’t even cry. The patient abandons activities which in the past were a source of joy and gives up interest in life. Patients with more severe depression are indifferent even concerning their children or spouse and isolate themselves. The difference from the flat (blunted) affect seen in schizophrenia is that anhedonia is itself painful. As depression starts remitting, anhedonia is one of the first symptoms to remit.

• Elevated mood refers to a state of elation, overconfidence, and enjoyment, with the person being cheerful, laughing and making happy and expressive gestures. It is not always pathological.

• Euphoria refers to a pathologically too much elevated mood that is inappropriate to real events. It is considered to constitute the opposite pole of "depressed mood" with "normality" in the middle. Experiencing a euphoric mood is pleasant thus patients are reluctant to receive treatment.

• Expansive mood is a condition with the patient expressing his/her feelings without restraint and control and behavior is usually colored by grandiose thoughts.

• Emotional lability refers to unstable and rapidly changing emotions because of hyper-reactivity to environmental stimuli. It is not always pathological

• Irritable mood is a state in which the person is easily annoyed by external stimuli and expresses anger and hostility at a low threshold. The presence of an irritable mood is often the cause for misdiagnosis of the patient, especially in combination with lability and mixed states.

Psychomotor Disorder

• Flight of ideas refers to an acceleration of the thinking processes, and it manifests itself in the form of rapid speech. Speech can be coherent and thoughts unusually sharp. However, when speed is excessively high, they both become incoherent and fragmented with content changing abruptly. Associations can be based on rhyme or chance perceptions.

• Psychomotor acceleration is considered to be the hallmark of mania, characterized by excessive activity (which is goal directed, high energy and endurance) as well as rapid, pressured speech.

• In comparison, psychomotor agitation also refers to a both mental and physical overactivity (pressured speech, restlessness, increased motor behavior) usually accompanied by a feeling of an inner turmoil or severe anxiety, with the intensity being so great that in spite of the fact that the patient has normal arousal, most if not all of this activity is purposeless.

• Psychomotor slowing means that the patient is inert and slow, both physically and mentally, but this does not always have an effect on overall performance although everything is done with much effort

• When psychomotor slowing is excessive, then psychomotor retardation appears and it includes reduction or disappearance of spontaneous motor activity, slumped posture and gaze, reduced and slow speech, and great fatigue.

• Stupor appears in younger patients when the psychomotor retardation is so extreme that they are unable to perform even basic everyday tasks. In more severe cases, motoric immobility occurs.

• Catatonia is defined as a complex condition which can include diverse symptoms and signs such as motoric immobility or on the contrary excessive purposeless motor activity not influenced by external stimuli, motiveless negativism, mutism, peculiar or stereotyped movements, mannerisms, grimacing and sometimes echolalia or echopraxia.

• Fatigue is a common problem in all mental disorders but especially in mood disorders and includes feeling tired or weak, sleepy, and sometimes irritable.

Neurocognitive Disorder

The term "neurocognitive" is often used with reference to higher cognitive function, such as attention, concentration, memory, praxis etc., and in psychiatry in contrast to the term "cognitive" which often is used with reference to the thought content or style and relates to cognitive therapy. Bipolar patients constitute a clinically heterogeneous group. However, they seem to perform poorly on most neuropsychological tests in comparison to healthy controls. They seem to suffer from deficits especially related to attention, inhibitory control, spatial working memory, semantic verbal fluency, verbal learning and memory, and maybe executive function (especially when considering the more severe and psychotic end of the bipolar spectrum). Verbal memory and probably executive function impairments may represent a trait rather than a state marker (Martinez-Aran et al. 2007; Martinez-Aran et al. 2008).

In extreme cases, neurocognitive disorder is so severe, especially in elderly patients that the picture resembles that of a dementing disease, thus is called "pseudodementia." However, it seems that at least half of these patients do in fact suffer from a dementing process at its early stages and later they manifest a formal dementia syndrome (Alexopoulos, Meyers, Young, Mattis, & Kakuma, 1993; Alexopoulos, Young, & Meyers, 1993; Bajulaiye & Alexopoulos, 1994; Reifler, 2000; Saez-Fonseca, Lee, & Walker, 2007) If one looks at the problem from another point of view, depression with mild cognitive disorder may be either the first manifestation or a risk factor for the development of dementia, especially when combined with a family history of dementia (Tsolaki, Fountoulakis, Chantzi, & Kazis, 1997; VanOjen & Hooijer, 1995; VanOjen, Hooijer, & . , 1995).

Thought Disorder

• Depressive thought content: depressed patients are characterized by a negative evaluation of the self, the world, and the future (the negative cognitive triad). In this frame, the depressive thought content includes pessimism, low self-esteem and low self-confidence, ideas of loss, deprivation and guilt, helplessness and hopelessness, and ultimately thoughts of death and suicide. The extent to which this negative way of thinking is primary or secondary is a matter for debate.

• Clang association: refers to the condition when the patient’s thoughts association and subsequently the speech are directed by the sound of a word rather than by its meaning. Therefore, words are not connected in a logical way and punning and rhyming serve as the drive.

• Thoughts of guilt concern self-reproach, self accussation and feeling the need for punishment. Thoughts and feelings of guilt are to largely normal and they can appear during a mood disorder because of the disability the disorder causes and the inability of the patient to fulfill his/her obligations towards significant others. In this frame patients may also feel shame. However, when the intensity and the content is excessive or even inappropriate then thoughts of guilt should be considered to be part of the symptoms and in more severe cases these thoughts may take on a delusional character.

• Thoughts of death are particularly important because they may eventually lead to suicidal behavior. The common belief that inquiring about such thoughts provokes suicidal behavior has no scientific basis. On the contrary, patients are often relieved this way. These thoughts include thoughts that the person will die and often the wish to die in some way so as to leave the suffering behind; this way they lead to suicidal ideation.

• Suicidal ideation refers to specific thoughts of killing oneself. It has many different forms, ranging from indirect expression (e.g., a wish not to wake up, or to die from a disease or an accident), to suicidal obsessions (urges or impulses to destroy oneself) and finally to elaborate planning of suicide. Some patients behave in a passive self-destructing way (e.g., careless driving or walking) while others plan their death in detail leaving notes and making sure no help will come on time.

• Manic thinking is excessively positive and optimistic. It is characterized by inflated self-esteem, grandiose sense (concerning importance, power, knowledge, or identity), over-confidence and sense of high achievements and abilities. Manic patients are refractory to explanations, confrontation, and to a significant extent they lack self-examination and insight; because of this lack of insight, mania nearly always, sooner or later acquires a delusional character.

Psychotic Symptoms

Psychotic features include delusions and hallucinations and both can be mood congruent or non-congruent depending on their content. Mood congruent psychotic features include those entirely consistent with the thought content (either manic or depressive) while mood incongruent are largely unrelated to it. Psychotic features are not uncommon in mood disorders, especially in bipolar disorder and delusions are relatively more common than hallucinations.

• Mood-congruent depressive delusions: often depressed thoughts can acquire a delusional severity and delusions congruent with depressive mood appear. Their content concerns inappropriate or over-exaggerated thoughts of guilt, sin, worthlessness, poverty and somatic health. Delusions concerning persecution and jealousy, although seemingly non-congruent, can also be mood congruent if they can be explained by, or strongly related to, thoughts of sin, guilt, jealousy or worthlessness. This kind of delusional thought makes a parent kill his/her family so as to save them from moral or physical corruption and then he/she commits suicide.

• Nihilistic delusions (Cotard delusion or Cotard's syndrome, negation delusion are related to depressive mood and concern the delusional belief that all or parts of the patient’s body are missing or rotten or decomposing, their internal organs are rotten or solidifying or are actually dead; the world and everything related to it have ceased to exist.

• Mood-congruent manic delusions: during manic episodes usually the thought content becomes delusional and includes delusions of exceptional mental and physical fitness or special talents. It may also include delusions of wealth, some kind of grandiose identity or importance. Sometimes the delusion can be so excessive that the identity itself changes (e.g., the patient believes that he is the incarnation of a messiah or a prophet etc.) Delusions of reference and persecution are considered to be mood-congruent on the basis of the belief that jealousy of the others at their special abilities is the cause of problems.

• Mood-incongruent delusions: various delusional ideas seemingly non-congruent (e.g., ideas of persecution or reference) can eventually be understood as arising from the grandiose sense of self and the belief of the patient that this importance causes the others to envy. However, sometimes there are delusions with no association to current mood (e.g., bizarre delusions without contextual relationship to mood). Sometimes a mixed mood episode can manifest itself with mood-incongruent delusions e.g., grandiose delusions in the presence of depressed mood.

• Depressive mood-congruent hallucinations are hallucinations consistent with either a depressed (e.g., voices accusing or humiliating) or manic mood (e.g., voices praising). Depressive mood-congruent hallucinations have an unpleasant content and they cause significant additional distress to the patient. Sometimes they command the patient to commit suicide and even dictate the method.

• Manic mood-congruent hallucinations: sometimes a manic mood causes such a vivid internal experience that the patient feels he/she can hear or see his/her own thoughts (e.g., hear hymns or live in the paradise).

• Mood-incongruent hallucinations refer to hallucinations unrelated to the current mood state.

• Insight: classically, depressive episodes are characterized by a fair degree of insight with the exception of the more severe psychotic cases. On the contrary, manic episodes are routinely characterized by a significant lack of insight and thus clinicians must routinely obtain basic information from significant others. This lack of insight may lead to refusal of treatment and to the need for involuntary admission to hospital.

Somatic and Neurovegetative Symptoms

Depressed patients often manifest changes in appetite, sleep and sexual functioning. Circadian rhythms are also disrupted. The classical notion of depression which is closer to melancholia includes reduction in all these functions; however, recently the "atypical" form of depression was described and this form includes an increase in these neurovegetative functions; that is overeating and oversleeping along with interpersonal rejection sensitivity which is a "personality-like" feature.

• Anorexia and weight loss: are considered to be reliable signs of depression. They can both be considered in the frame of a generalized inability to enjoy things (anhedonia). Weight loss is seen sometimes in paranoid patients who are afraid that food is poisoned and this should not be confused with anorexia and weight loss in the frame of depression. Weight loss is also frequent in cases of malignant disease so a full medical investigation should accompany any patient with changes in appetite or weight.

• Weight gain has been, relatively recently, recognized as a depressive feature and could be the result of overeating, decreased activity, or both. Apart from its devastating effect on the self-confidence and self-image, it can worsen the general somatic health especially in patients that become obese and suffer from metabolic syndrome.

• Insomnia is one of the hallmarks of depression and one of its most disturbing features. There are many types of insomnia that is, difficulty falling asleep (initial insomnia), multiple awakenings during the night (middle insomnia) or early morning awakening (terminal insomnia). Insomnia prolongs the depressive agony round the clock. Some patients try to self-medicate and solve the problem by alcohol or drug abuse (sedatives or hypnotics) but both eventually worsen the problem, partially because of tolerance and dependence problems and partially because they both further destroy the architecture of sleep. Unipolar depressed patients tend to exhibit insomnia stereotypically episode after episode and characteristically, in spite of extreme fatigue, they rarely oversleep.

• Hyposomnia: the term suggests a decreased need for sleep. That is, the patient feels energetic on awakening even though he slept for short periods. Some patients feel fresh and energetic even though he/she haven’t slept for days. This condition is usually seen during manic episodes and sometimes it heralds the beginning of such an episode.

• Hypersomnia: some patients, especially younger ones and females, often sleep too much and find it difficult to get up from the bed in the morning. Along with the other atypical features it is considered to be a marker for an underlying bipolar illness even in cases where no other bipolar feature is present. This condition should be differentially diagnosed from a number of medical conditions including narcolepsy and the Klein-Levin syndrome. In spite of prolonged sleep, depressed patients are characteristically tired in the morning, meaning that even prolonged sleep is not refreshing for them. The change in the pattern of sleep disruption with insomnia alternating with hypersomnia or hyposomnia suggests the presence of a bipolar illness rather than a unipolar depression.

• Circadian dysregulation: although many circadian functions can be disrupted in depressed patients, mainly the disturbance of sleep rhythms has been adequately studied. This disturbance includes deficits in delta sleep and more intense rapid eye movement (REM) activity during the first third of the night. A marked shortening of REM latency (that is the time from the onset of sleep to the first REM period) is considered to be characteristic for depression of any type, and seen even in remitted depressive patients and their healthy relatives.

• Seasonality: seasonal (especially autumn-winter) emergence or worsening of depression has been recognized since antiquity and mood has been related to the period of the year. Most patients seem to experience increased energy and activation during spring and the opposite during the fall and winter. Usually patients with strong seasonality also have reverse neurovegetative symptoms (fatigue, crave sugars, overeat and oversleep). In some patients seasonality is so concrete and important that modern classification includes a seasonal pattern for mood disorders.

• Sexual dysfunction: depressed patients classically report a decreased sexual desire and activity while additionally some women manifest a temporary interruption of their menses. Sexual dysfunction especially in females can lead to marital conflict and a psychodynamic/psychotherapeutically oriented therapist can mistakenly ascribe depression to the marital conflict with profound negative effects on the therapeutic outcome. Treating the sexual dysfunction or its consequences and leaving depression untreated is not uncommon and includes even surgical or unusual therapeutic interventions. An additional problem is that treatment with antidepressants often has sexual dysfunction as an adverse effect. The recent emergence of agents that treat impotence (e.g., sildenafil, tadalafil) could add a new method to treat this problematic symptom but this should never move the focus of treatment away from depression.

• Increased sexual desire and activity is typical for manic episodes, but also a subgroup of depressed patients may manifest increased sexual drive or activity and usually they also manifest other atypical or "reversed" features. Therefore, if seen in the frame of depression it heralds the presence of a depressive mixed episode. The increased sexual appetite usually leads to sexual indiscretion accompanied by a risky sexual life, often leading to marital problems, multiple separations or divorces, alcohol and drug abuse, gambling and sexually transmitted diseases like AIDS.

Behavioral Disorder

• Logorrhea refers to pressured, excessive and not always coherent speech, which is often uncontrollable. It is observed during manic episodes. Speech can be completely incomprehensible, with destroyed syntax and loose associations, often posing diagnostic dilemmas (e.g., from stroke). Other similar terms used are tachylogia, verbomania, volubility.

• Impulsive behavior: during mood episodes, either manic, depressive or mixed, patients tend to exhibit impulsive behavior. Especially during manic episodes they tend to be impulsive, disinhibited, and meddlesome. They are intrusive with increased involvement with others, poor social judgment and engage in a variety of activities without control or restraint (including aggression, sex, gambling, drug and alcohol abuse, spending, making gifts, risk taking, travelling etc.) Impulsive behavior is symptom that causes most problems and especially financial and interpersonal. In some cases even suicide may be acted on an impulsive basis.

The terms "endogenous depression," "neurotic depression," "anxious depression," "involutional melancholia," "psychotic depressive reaction" are not included in modern classification systems for a variety of reasons. The term "neurasthenia" is maintained in ICD-10 but its meaning is vague.

It seems that the psychotic melancholic subtype is the most stable type of depression repeating itself across episodes (Coryell et al. 1994). Almost a third of all major depressive episodes do not recur and it seems that recurrent depression is more familial with on average 6 months episode duration and a varying inter-episode interval length. A significant proportion of patients remain symptomatic and disabled, many of them suffering from subsyndromal depression (Judd et al. 1998). Around 15% develops psychotic features

Comorbidity

Large epidemiological studies and clinical experience suggest that mood disorders either co-exist or overlap considerably with anxiety disorders. Anxiety disorders can occur during a depressive episode, may be a precursor to it, or may appear during the future course of a mood disorder. Several authors suggest there is a common diathesis connecting mood and anxiety disorders with more recent data suggesting a strong link between BD-II and panic, obsessive-compulsive disorder, and social phobia.

All mood disorders but especially bipolar disorder are highly likely be comorbid with alcohol and drug (mainly stimulants) abuse, usually in the frame of a self-treatment effort from the side of the patient (Winokur et al. 1998).

Somatic illness frequently co-exists with depression and anxiety and the mood disorder has a profound negative impact on the outcome of the somatic illness. The therapist should also suspect clinical depression in all patients who refuse to participate in medical care.

Classification

The International Classification of Diseases, 10th version (ICD-10) includes sets of criteria for mood disorders, which are used throughout the world and constitute the official method of reporting health statistics. They are overlapping with the Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria; however, important differences do exist.

The basis of the classification in both systems is the definition of the depressive and manic/hypomanic episodes. The two systems describe mood disorders as follows:

In the ICD-10 the depressive episode is defined as follows:

A. DEPRESSIVE EPISODE

General criteria for a depressive episode:

G1. The depressive episode should last for at least 2 weeks.

G2. There have been no hypomanic or manic symptoms sufficient to meet the criteria for hypomanic or manic episode (F30._) at any time in the individual's life.

G3. Most commonly used exclusion clause. The episode is not attributable to psychoactive substance use (F10-F19) or to any organic mental disorder (in the sense of F00-F09).

F32: Depressive episode

A. The general criteria for depressive episode (F32) must be met.

B. At least two of the following three symptoms must be present:

(1) depressed mood to a degree that is definitely abnormal for the individual, present for most of the day and almost every day, largely uninfluenced by circumstances, and sustained for at least 2 weeks;

(2) loss of interest or pleasure in activities that are normally pleasurable;

(3) decreased energy or increased fatigability.

C. An additional symptom or symptoms from the following list should be present, to give a total of at least: four for mild (F32.0), six for moderate (F32.1) and eight for severe (F32.2 or F32.3 - depending on psychotic symptoms)depressive episode:

(1) loss of confidence or self-esteem;

(2) unreasonable feelings of self-reproach or excessive and inappropriate guilt;

(3) recurrent thoughts of death or suicide, or any suicidal behavior;

(4) complaints or evidence of diminished ability to think or concentrate, such as indecisiveness or vacillation;

(5) change in psychomotor activity, with agitation or retardation (either subjective or objective);

(6) sleep disturbance of any type;

(7) change in appetite (decrease or increase) with corresponding weight change.

A fifth character may be used to specify the presence or absence of the "somatic syndrome":

F32.x0 Without somatic syndrome

F32.x1 With somatic syndrome

F32.2: Without psychotic symptoms (only for severe depressive episode)

F32.3: With psychotic symptoms (only for severe depressive episode)

F32.3: Severe depressive episode with psychotic symptoms

A. The general criteria for depressive episode (F32) must be met.

B. The criteria for severe depressive episode without psychotic symptoms (F32.2) must be met with the exception of criterion D.

C. The criteria for schizophrenia (F20.0-F20.3) or schizoaffective disorder, depressive type (F25.1), are not met.

D. Either of the following must be present:

(1) delusions or hallucinations, other than those listed as typically schizophrenic in criterion G1(1)b, c, and d for general criteria for F20.0-F20.3 (i.e., delusions other than those that are completely impossible or culturally inappropriate and hallucinations that are not in the third person or giving a running commentary); the commonest examples are those with depressive, guilty, hypochondriacal, nihilistic, self-referential, or persecutory content;

(2) depressive stupor.

A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with mood:

F32.30: With mood-congruent psychotic symptoms (i.e., delusions of guilt, worthlessness, bodily disease, or impending disaster, derisive or condemnatory auditory hallucinations)

F32.31: With mood-incongruent psychotic symptoms (i.e., persecutory or self-referential delusions and hallucinations without an affective content)

F32.8: Other depressive episodes: Episodes should be included here which do not fit the descriptions given for depressive episodes, but for which the overall diagnostic impression indicates that they are depressive in nature. Examples included fluctuating mixtures of depressive symptoms (particularly those of the somatic syndrome) with nondiagnostic symptoms such as tension, worry, and distress, and mixtures of somatic depressive symptoms with persistent pain or fatigue not due to organic causes (as sometimes seen in general hospital services).

F32.9: Depressive episode, unspecified

Somatic syndrome

Some depressive symptoms are widely regarded as having special clinical significance and are here called "somatic" (terms such as biological, vital, melancholic, or endogenomorphic are used for this syndrome in other classifications). A fifth character may be used to specify the presence or absence of the somatic syndrome. To qualify for the somatic syndrome, four of the following symptoms should be present:

(1) marked loss of interest or pleasure in activities that are normally pleasurable;

(2) lack of emotional reactions to events or activities that normally produce an emotional response;

(3) waking in the morning 2 hours or more before the usual time;

(4) depression worse in the morning;

(5) objective evidence of marked psychomotor retardation or agitation (remarked on or reported by other people); (6) marked loss of appetite;

(7) weight loss (5% or more of body weight in the past month);

(8) marked loss of libido.

In The ICD-10 Classification of Mental and Behavioural Disorders: Clinical descriptions and diagnostic guidelines, the presence or absence of the somatic syndrome is not specified for severe depressive episode, since it is presumed to be present in most cases. For research purposes, however, it may be advisable to allow for the coding of the absence of the somatic syndrome in severe depressive episode.

The DSM-IV-TR definition of the depressive episode is similar in essence to the ICD-10 definition; however there are some differences. The time duration of 2 weeks is the same, but the first set of criteria to be met (the equivalent of criterion B) includes only the first two, that is depressed mood and loss of pleasure and not decreased energy, and demands either of them to be present in contrast to ICD which demands two out of three. The list of depressive symptoms of DSM-IV-TR does not include "loss of confidence or self esteem" and demands five out of a total of nine to be present. There is a definition for "mild" (up to 6 symptoms) but the definition of "moderate" and "severe" episodes are based rather on global disability. Most criteria include a more explicit time and intensity description, e.g., "nearly every day." ICD-10 demands symptoms do not fulfill the diagnosis of a manic/hypomanic episode while DSM-IV-TR demands the same for a mixed episode, but in essence it is the exactly the same. DSM-IV-TR includes the need of a functional impairment and that symptoms are not better accounted by bereavement. Both systems accept the possibility of the presence of mood congruent or incongruent psychotic symptoms; however while the ICD-10 implies that specific psychotic symptoms are more or less pathognomonic of a schizophrenia-like psychosis (like hallucinations giving a running commentary), the DSM-IV-TR accepts all kind of psychotic experiences in the frame of a mood episode. This creates a profound difference in the way the two systems define the boundary between psychotic mood disorder and schizoaffective disorder, and define the latter in a very different way. Another important difference between the two systems is that the ICD-10 defines the "somatic syndrome" while the DSM-IV-TR the "melancholic features." Both definitions are an attempt to include an "endogenous/melancholic-like" subgroup in the classification. It seems that the DSM-IV-TR definition is closer to this, while the ICD-10 definition includes too many anxiety and non-specific symptoms. Also the DSM-IV-TR includes the "atypical features" on the basis of mood reactivity, interpersonal rejection sensitivity and reversed neurovegatative symptoms. It seems that the DSM approach has higher reliability (Fountoulakis et al. 1999). Also catatonic features and postpartum onset are distinct specifiers for DSM.

B. MANIC EPISODE

F30.0: Hypomania

A. The mood is elevated or irritable to a degree that is definitely abnormal for the individual concerned and sustained for at least 4 consecutive days.

B. At least three of the following signs must be present, leading to some interference with personal functioning in daily living:

(1) increased activity or physical restlessness;

(2) increased talkativeness;

(3) distractibility or difficulty in concentration;

(4) decreased need for sleep;

(5) increased sexual energy;

(6) mild overspending, or other types of reckless or irresponsible behavior;

(7) increased sociability or overfamiliarity.

C. The episode does not meet the criteria for mania (F30.1 and F30.2), bipolar affective disorder (F31._), depressive episode (F32._), cyclothymia (F34.0), or anorexia nervosa (F50.0).

D. Most commonly used exclusion clause. The episode is not attributable to psychoactive substance use (F10-F19) or to any organic mental disorder (in the sense of F00-F09).

F30.1: Mania without psychotic symptoms

A. Mood must be predominantly elevated, expansive, or irritable, and definitely abnormal for the individual concerned. The mood change must be prominent and sustained for at least 1 week (unless it is severe enough to require hospital admission).

B. At least three of the following signs must be present (four if the mood is merely irritable), leading to severe interference with personal functioning in daily living:

(1) increased activity or physical restlessness;

(2) increased talkativeness ("pressure of speech");

(3) flight of ideas or the subjective experience of thoughts racing;

(4) loss of normal social inhibitions, resulting in behavior that is inappropriate to the circumstances;

(5) decreased need for sleep;

(6) inflated self-esteem or grandiosity;

(7) distractibility or constant changes in activity or plans;

(8) behavior that is foolhardy or reckless and whose risks the individual does not recognize, e.g., spending sprees, foolish enterprises, reckless driving;

(9) marked sexual energy or sexual indiscretions.

C. There are no hallucinations or delusions, although perceptual disorders may occur (e.g., subjective hyperacusis, appreciation of colors as especially vivid).

D. Most commonly used exclusion clause. The episode is not attributable to psychoactive substance use (F10-F19) or to any organic mental disorder (in the sense of F00-F09).

F30.2: Mania with psychotic symptoms

A. The episode meets the criteria for mania without psychotic symptoms with the exception of criterion C.

B. The episode does not simultaneously meet the criteria for schizophrenia (F20.0-F20.3) or schizoaffective disorder, manic type (F25.0).

C. Delusions or hallucinations are present, other than those listed as typically schizophrenic in criterion G1(1)b, c and d for F20.0-F20.3 (i.e., delusions other than those that are completely impossible or culturally inappropriate, and hallucinations that are not in the third person or giving a running commentary). The commonest examples are those with grandiose, self-referential, erotic, or persecutory content.

D. Most commonly used exclusion clause. The episode is not attributable to psychoactive substance use (F10-F19) or to any organic mental disorder (in the sense of F00-F09).

F30.20: With mood-congruent psychotic symptoms (such as grandiose delusions or voices telling the individual that he or she has superhuman powers)

F30.21: With mood-incongruent psychotic symptoms (such as voices speaking to the individual about affectively neutral topics, or delusions of reference or persecution)

F30.8: Other manic episodes

F30.9: Manic episode, unspecified

The DSM-IV-TR definition of the manic episode does not include a specific criterion for sexual behavior and condenses three ICD-10 criteria (#1, 4 and 8) into two. In essence the definitions are almost identical also requiring the same time duration. However, while in the ICD-10 the definition of hypomania requires a different set of criteria, in DSM-IV-TR hypomania differs from mania only in the duration which is at least 4 days and in the criterion suggesting a milder impairment in comparison to mania. Maybe the ICD-10 definition includes some cases which could be subthreshold for DSM-IV-TR. The DSM-IV-TR includes criteria concerning the impairment severity and suggests that hypomania is a milder condition which however, is clearly different from the normal condition of the person and is observable by others. It also includes a note that hypomania caused by any somatic antidepressant treatment should not count towards the diagnosis of a bipolar disorder.

C. MIXED EPISODE

F38.0: Mixed affective episode

A. The episode is characterized by either a mixture or a rapid alternation (i.e., within a few hours) of hypomanic, manic, and depressive symptoms.

B. Both manic and depressive symptoms must be prominent most of the time during a period of at least 2 weeks.

The DSM-IV-TR definition demands the patient fulfills for at least 1 week the criteria both for a major depressive and a manic episode, thus this definition is far more rigid. Taking into account the fact that a significant number of patients might fulfill the ICD-10 criteria for mixed episode, but not the respective DSM-IV-TR definition, this difference in classification could make classifications by the two systems to deviate significantly. Both systems classify "ultra-rapid cycling" as mixed episodes.

On the basis of the existence or not of hypomanic, manic, depressive and mixed episodes and accompanying features and longitudinal course, the ICD-10 recognizes the following disorders:

D. DISORDERS

F33: Recurrent depressive disorder

• current episode mild, with/without somatic syndrome
• current episode moderate, with/without somatic syndrome
• current episode severe with/without mood-congruent/incongruent psychotic symptoms
• currently in remission
• Other recurrent depressive disorders
• Recurrent depressive disorder, unspecified

F31: Bipolar affective disorder

• current episode hypomanic
• current episode manic with/without mood-congruent/incongruent psychotic symptoms
• current episode moderate or mild depression with/without somatic syndrome
• current episode severe depression with/without mood-congruent/incongruent psychotic symptoms
• current episode mixed
• currently in remission
• Other bipolar affective disorders
• Bipolar affective disorder, unspecified

F34.0: Cyclothymia

A. There must have been a period of at least 2 years of instability of mood involving several periods of both depression and hypomania, with or without intervening periods of normal mood.

B. None of the manifestations of depression or hypomania during such a 2-year period should be sufficiently severe or long-lasting to meet criteria for manic episode or depressive episode (moderate or severe); however, manic or depressive episode(s) may have occurred before, or may develop after, such a period of persistent mood instability.

C. During at least some of the periods of depression at least three of the following should be present:

(1) reduced energy or activity;

(2) insomnia;

(3) loss of self-confidence or feelings of inadequacy;

(4) difficulty in concentrating;

(5) social withdrawal;

(6) loss of interest in or enjoyment of sex and other pleasurable activities;

(7) reduced talkativeness;

(8) pessimism about the future or brooding over the past.

D. During at least some of the periods of mood elevation at least three of the following should be present:

(1) increased energy or activity;

(2) decreased need for sleep;

(3) inflated self-esteem;

(4) sharpened or unusually creative thinking;

(5) increased gregariousness;

(6) increased talkativeness or wittiness;

(7) increased interest and involvement in sexual and other pleasurable activities;

(8) overoptimism or exaggeration of past achievements.

Note. If desired, time of onset may be specified as early (in late teenage or the 20s) or late (usually between age 30 and 50 years, following an affective episode).

F34.1: Dysthymia

A. There must be a period of at least 2 years of constant or constantly recurring depressed mood. Intervening periods of normal mood rarely last for longer than a few weeks, and there are no episodes of hypomania.

B. None, or very few, of the individual episodes of depression within such a 2-year period should be sufficiently severe or long-lasting to meet the criteria for recurrent mild depressive disorder (F33.0).

C. During at least some of the periods of depression at least three of the following should be present:

(1) reduced energy or activity;

(2) insomnia;

(3) loss of self-confidence or feelings of inadequacy;

(4) difficulty in concentrating;

(5) frequent tearfulness; (6) loss of interest in or enjoyment of sex and other pleasurable activities;

(7) feeling of hopelessness or despair;

(8) a perceived inability to cope with the routine responsibilities of everyday life;

(9) pessimism about the future or brooding over the past;

(10) social withdrawal;

(11) reduced talkativeness.

Note. If desired, time of onset may be specified as early (in late teenage or the 20s) or late (usually between age 30 and 50 years, following an affective episode).

F34.8: Other persistent mood [affective] disorders

This is a residual category for persistent affective disorders that are not sufficiently severe or long-lasting to fulfill the criteria for cyclothymia (F34.0) or dysthymia (F34.1) but that are nevertheless clinically significant. Some types of depression previously called "neurotic" are included here, provided that they do not meet the criteria for either cyclothymia (F34.0) or dysthymia (F34.1) or for depressive episode of mild (F32.0) or moderate (F32.1) severity.

F34.9: Persistent mood [affective] disorder, unspecified

F38: Other mood [affective] disorders

There are so many possible disorders that could be listed under F38 that no attempt has been made to specify criteria, except for mixed affective episode (F38.00) and recurrent brief depressive disorder (F38.10). Investigators requiring criteria more exact than those available in Clinical descriptions and diagnostic guidelines should construct them according to the requirements of their studies.

F38.10: Recurrent brief depressive disorder

A. The disorder meets the symptomatic criteria for mild (F32.0), moderate (F32.1), or severe (F32.2) depressive episode.

B. The depressive episodes have occurred about once a month over the past year.

C. The individual episodes last less than 2 weeks (typically 2–3 days).

D. The episodes do not occur solely in relation to the menstrual cycle.

F38.8: Other specified mood [affective] disorders

This is a residual category for affective disorders that do not meet the criteria for any other categories F30-F38.1 above.

There are significant differences in the way the two systems conceptualize bipolar illness apart from the differences that occur because of different definitions of mood episodes. The DSM-IV-TR separates Bipolar I (which includes manic episodes) and Bipolar II (which includes hypomanic but not manic episodes) disorders on the base of the longitudinal history of the disorder. On the contrary, the ICD-10 distinguishes them only concerning the "current episode" irrespective of past episodes. The greatest difference concerning cyclothymia is that ICD-10 demands the presence of 3 out of 8 depressive or manic symptoms during the downs and up, while the DSM-IV-TR refers only to depressive and hypomanic symptoms from the list of criteria for major depressive and hypomanic episodes without any threshold. On the contrary the separate lists of symptoms criteria suggested by the ICD-10 differ significantly from the respected list for depressive episodes and hypomanic episodes and thus eventually the definitions of cyclothymia of the two classification systems differ significantly. The definition of DSM-IV-TR concerning dysthymia differs significantly from that of ICD-10 since it demands the presence of 2 out of 6 criteria in comparison to 3 out of 11 for ICD-10. The DSM-IV-TR criteria include appetite and weight changes and hypersomnia and not only insomnia. The ICD-IV-TR largely duplicates criteria although depending on the definition overlapping is not complete always (e.g., "depressed" and "frequent tearfulness;" "pessimism" and "hopelessness"). The DSM-IV-TR definition considers dysthymia to be a chronic mild form of depression while the ICD-10 stresses the cognitive and interpersonal impairment.

Classification of mood disorders due to a somatic disease or substance abuse:

F00-F09: Organic, including symptomatic mental disorders

F06.3: Organic mood (affective) disorder

F06.30: Organic manic disorder

F06.31: Organic bipolar disorder

F06.32: Organic depressive disorder

F06.33: Organic mixed affective disorder

F06.6: Organic emotionally labile (asthenic) disorder

F10-F19: Mental and behavioural disorders due to psychoactive substance use

F1x.54: Predominantly depressive symptoms

F1x.55: Predominantly manic symptoms

F1x.56: Mixed

Assessment

Mood disorders should be differentially diagnosed from a number of other morbid conditions, both psychiatric and non-psychiatric.

Several mental disorders including alcohol and substance use disorders, normal bereavement, depression in the frame of schizophrenia, anxiety disorders, personality disorders, dementia and a variety of general medical conditions that cause syndromes similar to depression should be differentiated from mood disorders. Also several drugs used for the treatment for a number of diseases might also cause depression. In general the prevailing opinion is that a missed diagnosis of mood disorder in favor of another mental diagnosis may mean that the patients does not receive proper treatment, which has serious consequences.

Maybe the most important differential diagnosis should be made between mood and personality disorders. Since the state dependency of most personality features is well documented (Grilo et al. 2004; Grilo et al. 2005; Gunderson et al. 2004; McGlashan, 1986; McGlashan et al. 2005; Morey et al. 2004; Stone, 1993, 2005; Warner et al. 2004), clinicians should avoid putting this diagnosis in patients with an active mood disorder, even in cases this mood disorder is subthreshold. A dangerous stereotypical thinking leads clinicians to suggest that because a patient does not respond adequately to usual treatment the disorder is personality-based. This is especially problematic concerning subthreshold or non-classic mixed clinical pictures which are relatively refractory to treatment and cause despair to the therapist.

Normal bereavement appears normally in persons experiencing the loss of a significant other and consists of several depressive symptoms during the first 1-2 years after the loss. But only around 5% will eventually progress to a depressive disorder. Normal bereavement is generally contrasted with depression because reactivity to the environmental stimuli is preserved, the disability if any is mild and no severe psychopathology (delusions or hallucination or true suicidal ideation) is present.

Anxiety symptoms commonly occur in mood patients, including panic attacks, fears, and obsessions. Longitudinal data suggest that although the depressive symptoms tend to remit by passing the time, the anxiety symptoms persist. Because anxiety disorders rarely appear after the age of 40 for the first time, a late appearance of significant anxiety should be considered to be a sign of depression. Transient and periodic monosymptomatic phobic and obsessional states that do not fulfill criteria for a formal disorder as conceptualized in either classification system should also be considered as reflecting an underlying mood disorder and should be treated accordingly.

Somatic complaints especially in depression might also reflect an underlying physical illness rather than a somatization mechanism. The somatic disorders most commonly related to depression are Multiple Sclerosis, Parkinson's disease, head trauma, epilepsy, sleep apnea, cerebral tumors, vascular encephalopathy, chronic fatigue syndrome, some collagen disorders like rheumatoid arthritis and lupus erythematosus and various neoplastic conditions like abdominal malignancies (especially in the pancreas) and disseminated carcinomatosis. Also there is a number of abnormal endocrine conditions including hypo- and hyperthyroidism, hyperparathyroidism, hypopituitarism, Addison's disease, Cushing's disease and diabetes mellitus, several infections like general paresis (tertiary syphilis), toxoplasmosis, influenza, viral pneumonia, viral hepatitis, infectious mononucleosis and AIDS, and nutritional conditions like pellagra and pernicious anemia.

A number of pharmacological agents used for the treatment of various diseases could cause depression or a depressive-like condition. These include a-methyldopa, anticholinesterase insecticides, cimetidine, cycloserine, indomethacin, mercury, phenothiazine antipsychotic drugs, reserpine, steroidal contraceptives, thallium, vinblastine and vincristine Withdrawal from agents like amphetamine, alcohol or sedative-hypnotics could also be the cause of depression.

In geriatric patients the differentiation between depressive pseudodementia and degenerative dementia is vital and is done by the neuropsychological profile of the patient as well as from the clinical course which in pseudodementia cases includes an acute onset without prior cognitive disorder, a personal or family history of affective illness, circumscribed memory deficits and an unstable cognitive dysfunction that can be reversed with proper coaching.

The need for the differential diagnosis of mood disorders from the above mentioned conditions makes important for the clinician to obtain a variety of laboratory examination data including standard blood and biochemical tests, EEG, ECG, thyroid function tests and in depending on availability and cost even brain MRI and in late onset cases indices assessing malignancy.

There are a large number of neuropsychological and psychometric tools available for the assessment of mood disorders and the clinician can choose which to use on the basis of his training and specific needs. However, a basic list includes the following tools:

Psychometric Tools

• Visual Analogue Scale (Rosenthal, Goldfarb, Carlson, Sagi, & Balaban, 1987): This is a very simple method, according to which, the examiner or the patient himself is asked to determine the quantity of the symptomatology on a bar 100 mm in length. One end of the bar is defined as "lack of depression" (0 mm) and the opposite one as "profound depression" (100 mm). The distance from the beginning (0 mm) is considered as the "degree" of depression. This method is has been in existence since 1921. A positive relationship between the subject’s ratings, the examiners’ opinion, and the score on the Beck Depression Inventory is reported. Today, it is considered somewhat outdated and not suitable for research purposes.
• Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960): This is the most widely known and used scale worldwide. It is examiner-rated. The basic scale includes 17 items, some of them assessing somatic symptoms, other assess anxiety or vegetative function and others could be contaminated by medication side effects. Therefore although it is a comprehensive scale, its use of this scale in somatic patients or the elderly patients has some limitations. It also under-assesses atypical depressive patients.
• Beck Depression Inventory (BDI-I) (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961): This is a widely used self-report scale that measures the thought content, or cognitive aspect of depression. It includes 21 items. Its properties when used in somatic patients or the elderly are less well known. A revised version (BDI-II) (Beck, Steer, Ball, & Ranieri, 1996) which is adjusted to modern classification is also available.
• Zung Depression Rating Scale (ZDRS) (Zung, 1965): This is an old self-report scale which reflects an older concept of depression that dominated during the 60s, and might not produce reliable and valid results in somatic patients and geriatric populations. It also under-assesses atypical depressive patients.
• Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 1979): This instrument was the product of the need for scales with high sensitivity to changes produced by antidepressant medication. It is rated by an examiner. As a result, it includes only 10 items and almost no "somatic" symptomatology. A significant drawback of this scale is that its content is restricted to those symptoms responsive to medication at the time of the design of the scale, and therefore it does not represent a global assessment of depression. Another drawback is that it was developed for use in younger and somatically healthy patients. The content and method of development of the scale might make its application in somatic patients and elderly individuals problematic and its application in this population may lead to erroneous conclusions.
• Geriatric Depression Scale (GDS) (Yesavage et al. 1982): It is the first scale especially designed for use in elderly populations. It is a self-report scale however, sometimes it is necessary to administer it through an interviewer. It exists in a 30-item and a 15-item form. It focuses mainly on the psychological concern of the patient and the way he/she perceives life, avoiding the assessment of somatic complaints.
• Center for Epidemiological Studies-Depression Scale (CES-D) (Radloff, 1977): It is a self-report instrument and one of the most widely used. It seems that it is this scale is least affected by somatic disorders and handicaps. It consists of 20 items. The validity of the CES-D might be compromised when used with somatic patients or elderly individuals, and modifications for its use in this population has been recommended.
• Young Mania Rating Scale (YMRS) (Young, Biggs, Ziegler, & Meyer, 1978): The YMRS is an 11-item scale used to assess the severity of mania in patients with a diagnosis of bipolar disorder. It takes 15-30 minutes to complete by a trained examiner. It is a reliable easy to use and simple tool, widely used. Some 4 items have double-rating which can lead to questions of reliability.
• The Bech-Rafaelsen Mania Rating Scale (MRS) (Bech, Rafaelsen, Kramp, & Bolwig, 1978): It consists of 11 items and assesses the severity of mania in bipolar patients. It is rated by an examiner.
• General Assessment of Functioning) (GAF): This is a scale introduced by the DSM classification system, that assesses global functioning in the psychological, family, social and occupational spheres and attempts to localize it on a continuum from 0 (full decline of functioning, the patient is dangerous to self or others) to 100 (supreme level of functioning). It shares many characteristics with the visual analog scale, and represents a non-specific way to quantify everyday functioning, but with low reliability and accuracy.
• General Assessment of Relational Functioning (GARF): It can be used to assess the patient’s family or the general environment in which he/she lives.
• Social and Occupational Functioning Assessment Scale (SOFAS): This is a scale for the assessment of functioning in work place and in social situations. Both GARF and SOFAS are introduced by DSM-IV, and share characteristics with GAF. Their major difference is that they have a restricted field of functioning to assess.
• Clinical Global Impression (CGI): This is a group of simple scales assessing symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. They include the Clinical Global Impression - Severity scale (CGI-S) which is a 7-point scale, the Clinical Global Impression - Improvement scale (CGI-I) which is a 7 point scale and the Clinical Global Impression - Efficacy Index which is a 4 point X 4 point rating scale
• TEMPS-A (Akiskal, Akiskal, Haykal, Manning, & Connor, 2005), NEO-PI (Costa & McCrae, 1997), TCI (Cloninger, Svrakic, & Przybeck, 1993) and the MMPI-2 (Butcher, Graham, & Fowler, 1991): They are self-report questionnaires that assess temperament, character and personality

The literature suggests there is no significant difference among the various self-administered instruments assessing depression in terms of performance and overall sensitivity is around 84% and specificity around 72% (Fountoulakis, Bech et al. 2007; Mulrow et al. 1995).

Neuropsychological Tools

The assessment of neurocognitive function is very important especially for psychogeriatric patients even in cases without observable symptoms or signs of "organic" disorder or dementia. Scales for rapid screening of cognitive disorder are the following:

• Mini Mental Status Exam-(MMSE) (Folstein, Folstein, & McHugh, 1975): It is a brief mental status examination designed to quantify cognitive status by assessing performance on the following cognitive domains: orientation, language, calculation, memory and visuospatial reproduction thus providing a brief measure of global cognitive functioning.
• The Cambridge Cognitive Examination For The Elderly-(CAMDEX) (Roth et al. 1986): It includes a large number of items covering almost every aspect of the patient's medical history as well as his/her family medical history. It also includes evaluation of the patients’ current condition concerning both physical and mental health. Sixty-eight of these items constitute the CAMCOG scale, which is the part of CAMDEX examining the patient's cognitive functions. The MMSE score is simultaneously obtained. CAMCOG includes eleven subscales. Each one evaluates a "different" cognitive function of the patient: Orientation, Language/Comprehension, Language/Expression, Remote Memory, Recent Memory, Learning, Attention, Praxis, Calculations, Abstract Thinking and Perception.
• Weschler Memory Scale-Revised (D'Elia, Satz, & Schretlen, 1989) Maybe the most global and comprehensive scale for the assessment of memory. Its greatest drawback is that it is time consuming. It includes testing of Personal and current information, Orientation, Mental Control, Logical Memory, Digits forward and backward, Visual reproduction and Associated learning.
• Weschler Adult Intelligence Scale - Revised (WAIS-R): The WAIS-R gives a global Intelligence Quotient (IQ) and also two subscales: verbal and performance.
• Clock Drawing Test (Sunderland et al. 1989): This is a simple test which demands the patient to draw a clock. It can be used as a screening tool especially for dementia. The test requires multiple cognitive functions to co-operate.
• Verbal Fluency Test : The test demands the patient to name as many objects and animals is able to within a time frame of 1 minute.
• Trail Making Test (Reitan, 1971): The first form of is test demands the patient to trail the sequence of numbers put at random places on paper by using a pencil, while the second form demands to alternate between numbers and letters randomly put on paper. The time needed to fulfill each of the two tasks is recorded. The test is an assessment of general mental function.

Pathogenesis

Today most mood disorders experts agree that mood disorders have both endogenous and exogenous components and in most patients they are both present. After the historical dualism suggested by Rene Descartes in the 17th century, only as recent as the early 20th century Adolf Meyer used the term "psychobiology" to emphasize that psychological and biological factors interact in the development of mental disorders. The bio-psycho-social model has been proposed by Engel (Engel, 1977, 1980) and provides a non specific but inclusive theoretical framework in order to host all variables suggested by various approaches to cause depression.

Social Stressors

Although lay people and much of psychological theories attribute mood disorders to adverse life events, there are several studies which dispute the role stressful life events play in the development or the course of depression (Harkness & Luther, 2001; E. Paykel, Rao, & Taylor, 1984). But the sensitization of stress-responsive neurobiological systems as a possible consequence of early adverse experience has been more solidly implicated in the pathophysiology of mood and anxiety disorders. A history of childhood abuse per se may be related to increased neuroendocrine stress reactivity, which is further enhanced when additional trauma is experienced in adulthood (Heim et al. 2002). In this frame, depressed patients were reported to have higher perceptions of day-to-day stressors (hassles), reduced perception of uplifting events, excessive reliance on emotion-focused coping strategies, and diminished quality of life in comparison to controls. Among depressed patients the hassles, coping styles and some elements of quality of life were related to symptom severity, as well as treatment-resistance (Ravindran, Matheson, Griffiths, Merali, & Anisman, 2002). The question that arises is whether this is a true fact or these patients (which have higher personality psychopathology and interpersonal rejection sensitivity) tend to over-report life events (Fountoulakis, Iacovides, Kaprinis, & Kaprinis, 2006).

Thus, many authors insist that psychosocial factors are relatively unimportant in the subsequent course of severe and recurrent depressions, in contrast to their contribution to onset of such depressions and subsequent outcome of milder depressions (Paykel, Cooper, Ramana, & Hayhurst, 1996; Thomson & Hendrie, 1972).

Psychological Models of Mood Disorders

There are a number of psychological models proposed during the last 100 years to explain the pathogenesis of depression. The most important are the following:

1. Aggression-Turned-Inward Model: It has been proposed by Sigmund Freud and Karl Abraham on the basis of a "metaphor" from physics to psychology ("hydraulic mind"). According to this model, during the oral phase (that is, during the 12-18th months of life) disturbances in the relationship between the infant and the mother establish a vulnerability to develop depression. Then during the adult life, a real or imaginary loss leads to depression as the result of aggressive impulses turned inward and directed against the ambivalently loved internalized object which had been lost. The aim of that turned-inwards aggression was supposed to be the punishment of the love object which fails to fulfill the patient’s need to be loved. It is therefore accompanied by guilt which could lead to suicidal behavior. Later other authors proposed somewhat different versions of this model. The drawbacks of this model include that it represents a relatively closed circuit independent of the outside world, while the clinical fact is that many depressed patients openly express anger and hostility against others which is reduced after treatment, and that there are no evidence supporting the concept that expressing anger outwards has a therapeutic effect in the treatment of clinical depression behavior

2. Object Loss: The term refers to traumatic separation from significant objects of attachment. However, according to empirical research data, only a minority of no more than 10% of people experiencing bereavement will eventually manifest clinical depression. Thus the model includes two steps; an early one which includes significant loss during childhood thus creating a vulnerability which during the second step, that is significant loss during adult life, leads to clinical depression. This model fits better the data in comparison to the aggression-turned-inward and has some support by studies on primates although the latter point to a broad psychopathology rather than specifically depression.

3. Loss of Self-Esteem: Depression is considered to originate from the inability of the ego to give up unattainable goals and ideals resulting in a collapse of self-esteem. This model suggests that the narcissistic injury that destroys the patient’s self-esteem comes from the internalized values of the ego rather than the hydraulic pressure deriving from the id as proposed by the aggression-turned-inward model. In this frame the loss of self-esteem has a sociocultural and existential dimension and thus this theory is testable to a significant extent. The drawback of this theory is that both persons with low and high self esteem can develop depression or mania without any significant differences among them.

4. Cognitive Model: The cognitive model was developed by Aaron Beck and suggests that thinking in a negative way is the core of clinical depression. According to this, depression is conceptualized in the frame of the "cognitive triad." This triad proposes that patients conceive the self, the environment and the future in a negative depressive way (helplessness, negative and hopelessness). In the core there seems to be bias of the person in the way of thinking and interpreting which results in a profound negative attributional style (mental schemata) which is considered to be global, internal, and stable. The bias in the way of thinking is because of overgeneralization, magnification of negative events with a simultaneous minimization of positive events, arbitrary inference, and selective abstraction. Systematic errors in thinking, allow the persistence of negative schemas despite contradictory evidence. The major drawback of this model is the fact that it is based on retrospective observations of depressed patients, thus the negative triad could be simply subclinical manifestations of depression and not the cause of it. The major advantage is that it led to the first testable and practical psychotherapeutic approach which seems to be effective in a specific subgroup of patients.

5. Learned Helplessness Model: This model is based on animal experiments and proposes that the depressive attitude is learned during past situations in which the person was not able to terminate or avoid undesirable or traumatic events. However, it seems that the learned helplessness paradigm is more general and refers to a broader mental condition (e.g, behavior, posttraumatic stress disorder etc.). It seems that past events could shape a personality profile which includes passivity, lack of hostility, and self-blame. However, this line of thinking could lead to the notion that depression and the behavior accompanying it should be considered to be a result of a masochistic lifestyle with manipulative behavioral patterns in order to handle interpersonal issues. Even more, recent animal research has implicated the importance of genetic factors in the vulnerability to learning to behave helplessly.

6. Depression and Reinforcement: According to the reinforcement the behavior characteristic of depression develop because of a lack of appropriate rewards and with receipt of non-contingent rewards. This theory bridges personality, low self esteem and learned helplessness with the human social environment; however it seems more appropriate for the interpretation of social issues than clinical depression. A psychotherapeutic approach aiming to improve the patient’s social skills is based on this theory.

7. Psychological theories of Mania: Most theories view manic symptoms as a defense against an underlying depression with the use of a number of defense mechanisms like omnipotence, denial, idealization, and contempt. In this frame, the euphoric state of the patient is understood as a tendency to extinguish any unpleasant aspects of reality and to disregard for the problems of reality, even if the situation is tragic. Thus mixed episodes are easily psychodynamically understood, since as manic elements seen in depressed patients are considered to be defenses.

Biological Models of Mood Disorders

Data coming from animal experiments and models implicate the limbic-diencephalic brain in mood disorders and more specifically neurons containing serotonin and noradrenaline. Historically the monoamine deficiency hypothesis is based on data from the study of the cerebrospinal fluid (CSF) metabolites. According to this theory, there is a monoamine deficiency, especially norepinephrine (NE), in depression. Later, studies illustrated that this theory should also include serotonin (5-HT), leading to a broader theory regarding neurotransmission disorder in Central Nervous System (CNS) (Maas, 1975; Schildkraut, 1965; Van Praag & Leijnse, 1963). Later, the cholinergic-noradrenergic imbalance hypothesis (Janowsky, el-Yousef, Davis, & Sekerke, 1972) included acetycloline in a broader model for mood disorders. More complex models include state changes (depending on the polarity of the mood episode) in the excitatory amino acid function in specific areas of the cortex (Fountoulakis, Giannakopoulos, Kovari, & Bouras, 2008).

However, in spite of decades of extensive research there is no definite proof for either a deficiency or an excess of either the quantity or the overall functioning of biogenic amines in specific brain structures. Even when these abnormalities were documented, it has been shown that they are neither necessary nor sufficient for the occurrence of mood disorders. In contrast, it seems that the neurotransmitter disorders recognized until today refer to a broader behavioral dysfunction which includes behavioral disinhibition, obsessive-compulsive symptoms, anxiety, eating disorders and substance and alcohol abuse as well as personality disorders. This is not peculiar since most classic animal models are in essence post-traumatic stress models and most biological psychoendocrinological markers are markers of stress-related somatic reactions. Recent research explores disturbances at the level of second messengers and close to DNA function with variable success but no definite conclusions.

A number of biological markers have been developed so far but no one is proved so far strong enough for use in clinical practice. The dexamethasone-suppression test (DST) has been widely used for the study of hypothalamus-pituitary-adrenal (HPA) axis disorders in patients with depression (Evans & Golden, 1987; Green & Kane, 1983; Stokes et al. 1984). It requires the oral administration of 1mg dexamethasone (a synthetic glucocorticoid) at 23:00 on day 1 and the assessment of cortisol levels at the same time, at 08:00, 16:00, and at 23:00 on day 2. A cortisol value of 5?g/dl, in at least one measurement in day 2, is considered to be the cut-off point between normal (suppressors) and pathological (non-suppressors). Longer protocols requiring higher dosage for dexamethasone and a 24 hour long assessment have also been suggested. The test presents a 67% sensitivity and 96% specificity in the diagnosis of melancholy in psychiatric inpatients. The results of the up to date research efforts report that DST presents results that are probably related with the severity of depression and the patient’s family history. Other psychoendocrinological markers are the TRH Stimulation Test (blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone) (Kendler, Thornton, & Gardner, 2000; Musselman & Nemeroff, 1996), the fluramine and d-fenfluramine challenge tests which (Di Renzo & Amoroso, 1989; Fessler, Deyo, Meltzer, & Miller, 1984; Garattini, Mennini, & Samanin, 1987, 1989; Invernissi, Berettera, Garattini, & Samanin, 1986; Ouattrone, Tedeschi, Aguglia, & Scopacasa, 1983; Quattrone, Schettini, & DiRenzo, 1979; Rowland & Carlton, 1986; Siever & Murphy, 1984; Zarifian, 1993) are supposed to reflect central serotonin activity (administration of 30 mg of the d-fenfluramine orally and measurement of prolactin plasma levels at the baseline and 60?, 120?, 180?, 240? and 300? after the administration), blunted growth hormone (GH) response to the a2-adrenergic receptor agonist clonidine (an index of noradrenergic dysregulation) and others. A non-endocrinological marker is based on EEG and concerns the observation that depressed patients are phase advanced in many biological rhythms, especially concerning the latency to the first rapid eye movement in sleep (shortened REM latency) (Kupfer, 1976).

A possible comprehensive model could suggest that mood patients have a deficit in the adequate mobilization of neurotransmitters when facing continued or repeated stress, and as a result, through a "kindling" effect (Kendler et al. 2000; Post, Weiss, & Pert, 1984, 1988; Post & Weiss, 1989; Post, Susan, & Weiss, 1992; Post & Silberstein, 1994; Post & Weiss, 1998), the mood change is intense, prolonged and not self-limited, and tends to be triggered by progressively unimportant events and finally automatically. Thus it is expected that an early application of treatment with antidepressants and psychotherapy could prevent neuroplastic changes and the long term worsening of the clinical course.

The data from family and twin studies argue strongly for the familial nature of mood disorders (Kendler, Pedersen, Johnson, Neale, & Mathe, 1993; Sadovnick et al. 1994). However, so far the mode of genetic transmission remains elusive. Several studies have focused on a functional polymorphism in the promoter region of the serotonin transporter serotonin transporter gene (HTTLPR) which is supposed to moderate the influence of stressful life events on depression and the brain derived neurotrophic factor (BDNF) which is supposed to exert a prophylactic effect against neuronal toxicity induced by stress (Belmaker & Agam, 2008; Caspi et al. 2003; Kato, 2007). The most possible model is a multifactorial-threshold model. The twin data suggest that genes account for 50-70% of the etiology of mood disorders.

Treatment

Mood disorders are not only formally distinguished into two major groups, that is unipolar and bipolar mood disorder, but also treatment differs between them. Even within the unipolar group different subcategories exist, that demand somewhat different treatment. Psychotherapy as monotherapy is generally reserved for milder cases while antidepressants are first choice for moderate to severe cases. Patients with psychotic features need adding antipsychotic. Bipolar patients need a core treatment with the so-called mood stabilizers and depending on the episode and the state of the clinical picture additional agents can be used.

Treatment is artificially separated into acute face treatment and maintenance. During the acute-phase the therapist should decide where the patient should be treated (e.g., outpatient, inpatient, day hospital etc). The decision is based on the assessment of issues like the risk of suicide, the patient’s insight, comorbidity, severity of impairment and the psychosocial support available. As a general rule, patients who respond to acute-phase treatment receive a similar treatment during the maintenance phase. During that phase, medication should be kept at the same dosage if possible.

Unipolar Mood Disorders

Psychotherapy

The first kind of available treatment for mood disorders was psychotherapy. Some kind of psychosocial, moral or psychotherapeutic intervention was available since antiquity; however only during the 20th century psychotherapy was systematically developed as a formal treatment.

A variety of psychotherapies are today available and to some extend have a proven efficacy in the treatment of mood disorders. Although there are still psychoanalytical and psychodynamic-oriented approaches, today most professionals prefer the more pragmatic, short term and focused approaches of behavioral or cognitive therapy or utilize an eclectic approach.

The evidence so far altogether seems enough to support the efficacy of psychotherapeutic strategies in mild and moderate depression but not in more severe cases. However, the evaluation of psychotherapies is not as good as that of antidepressants. Most psychotherapies, especially the psychodynamically oriented are not possible to be tested scientifically while the practical ones like cognitive and behavioral have not been tested under placebo conditions and it is doubtful this is possible (Cuijpers, van Straten, & Warmerdam, 2007a, 2007b; Hegerl, Plattner, & Moller, 2004; Paykel, 2007). Thus important questions remain concerning the use and usefulness of psychotherapy in mood disorders. Some authors suggest psychotherapies should be considered as equal alternatives to medication especially under the warning that antidepressants and maybe anticonvulsants provoke suicidality; however there are reports suggesting that even psychotherapy can also evoke suicidal thoughts (Moller, 1992).

There are no established clinical predictors to guide the choice of a specific kind of psychotherapy for the individual patient.

• Interpersonal therapy (ITP): It was developed by Gerald Klerman and Myrna Weissman and its basic concepts include accepting the patient to assume the sick role and focusing on improving the patient’s interpersonal functioning. Since depression can cause interpersonal problems, and vice versa interpersonal problems can precipitate depression, IPT focuses on solving these problems. It is a short-term psychotherapy (12-16 weekly sessions) and the therapeutic goals include reducing depressive symptoms (by an educational approach), improving self-esteem and helping the patient to develop more-effective copying strategies concerning social and interpersonal relations.

• Cognitive-behavioral therapy (CBT) was developed by Aaron Beck and is based on cognitive and behavioral psychology and the cognitive theory on the etiopathogenesis of depression. It aims at changing the way a person thinks and in this way it alleviates depression and prevents recurrence. It utilizes didactic methods and cognitive and behavioral techniques. The patient is encouraged to identify and challenge negative conditions, develop alternative, and more flexible cognitive schemas, and exhibit new behavioral patterns. It is a short-term, structured therapy and demands the active participation of the patient.

• The Behavioral therapy was developed by C.B. Ferster and is based on the work of B.F. Skinner, and the behavioral approach to the etiopathogenesis of depression. It puts the emphasis on the relationship between an observable behavior and the conditions that control or determine it. It also stresses the importance of the role of rewards. A major goal is increasing the frequency of positive reinforcing and decrease negative thus improving social and interpersonal skills.

Biological Treatment

The basis of "biological" treatment is antidepressants although Electro-Convulsive therapy (ECT) and total and partial sleep deprivation are also used in refractory cases. Other therapies which were used in the past and are considered to be effective, like insulin therapy, are no longer in use. The ability of psychiatrists to individualize treatment decisions and choose a specific antidepressant for a specific patient is poor and the choice is largely dependent on adverse effects and comorbid conditions. The therapeutic effect of antidepressants is evident after at least two weeks and therapy should be administered over the course months, or sometimes years.

Antidepressants appeared during the 1950s and the first one was imipramine introduced by Roland Kuhn. Although a variety of mechanisms have been proposed as responsible for the effectiveness of antidepressants, it seems that increasing the serotonin signal in the limbic system is what eventually survives as a concept. The role of norepinephrine seems to be important too, since its depletion cancels the effectiveness of antidepressants.

The major classes of antidepressant agents are:

• Tricyclics (TCAs): Tricyclic antidepressants are the oldest class of antidepressant drugs. This group includes imipramine, clomipramine, amitryptiline, nortriptyline and desipramine. They act by blocking the reuptake of a number of neurotransmitters including serotonin, norepinephrine and dopamine. Their side effects include increased heart rate, drowsiness, dry mouth, constipation, urinary retention, blurred vision, dizziness, cognitive disorder, confusion, skin rash, weight gain or loss and sexual dysfunction. TCAs can be lethal at overdose (over ten times the therapeutic dosage) usually due to cardiac arrhythmia. However, TCAs are highly effective and are still used especially in severe and refractory depression in spite of the development of newer agents which are safer and with fewer side effects.

• MonoAminOxidase Inhibitors (MAOIs) and Reversible Inhibitors of Monoamineoxidase A (RIMA): reversible" forms affecting only the MAO-A subtype Monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil) may be used if other antidepressant medications are ineffective. Because there are potentially fatal interactions between this class of medication and certain foods (particularly those containing Tyramine), red wine, as well as certain drugs, classic MAOIs are rarely prescribed anymore. MAOIs work by blocking the enzyme monoamine oxidase which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). MAOIs can be as effective as tricyclic antidepressants, although they can have a higher incidence of dangerous side effects (as a result of inhibition of cytochrome P450 in the liver). A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), acts in a more short-lived and selective manner and does not require a special diet. Additionally, (selegiline) marketed as Emsam in a transdermal form is not a classic MAOI in that at moderate dosages it tends to affect MAO-B which does not require any dietary restrictions. As one of the side effects is weight gain and could be extreme. block the break-down of monoamine neurotransmitters (serotonin and norepinephrine) by inhibiting the enzymes which oxidize them, thus leaving higher levels still active in the brain (synaptic cleft). liver inflammation, heart attack, stroke, and seizures. Serotonin syndrome is a side effect of MAOIs when combined with certain medications

• Selective Serotonin Reuptake Inhibitors (SSRIs): This class of antidepressants appeared in 1988 and includes fluoxetine, paroxetine, sertraline, citalopram and escitalopram and fluvoxamine. It acts presumably by selectively inhibiting the reuptake (by the presynaptic neuron) of serotonin (also known as 5-hydroxytryptamine, or 5-HT). In this way the synaptic levels of 5-HT increase. SSRIs typically have fewer side effects and a more favorable profile in comparison to the TCAs but also in comparison to other classes of antidepressants. Their adverse effects include headache, anxiety, insomnia, nervousness, decreased appetite, decreased libido, drowsiness, dry mouth and serotonin syndrome. There is some data suggesting SSRIs might not be as efficient as other classes especially in more severe cases of depression. Recently the Food and Drug Administration (FDA) has included a Black Box warnings on all SSRIs suggesting an increased like hood for suicidality in children and adolescents who are prescribed these drugs, although subsequent analysis and ecological studies consider this warning to be exaggerated and in some countries might already have led to an increase of the suicidal rate.

• Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): This is a new group that includes venlafaxine, duloxetine, milnacipram, nefazodone and maybe mirtazapine. These agents inhibit the reuptake of both the 5-HT and norepinephrine. Their side effect profile is more or less similar to that of the SSRIs. After acute discontinuation a withdrawal syndrome could occur. Some data suggest they are as class stronger than the SSRIs.

• Noradrenergic and specific serotonergic antidepressants (NASSAs): This group includes only mirtazapine and mianserin, and suggests it works through the increase of norepinephrine and 5-HT neurotransmission by blocking presynaptic alpha-2 adrenergic receptors while simultaneously minimizes 5-HT related side-effects by blocking specific serotonin receptors. The side effects include the typical SNRI side effects but also include a more pronounced drowsiness, increased appetite, and significant weight gain.

• Norepinephrine (noradrenaline) reuptake inhibitors (NRIs): This group includes reboxetine which exerts its effect via norepinephrine.

• Norepinephrine-dopamine reuptake inhibitors (NDRIs): This group includes bupropion which inhibits the reuptake of dopamine and norepinephrine.

The overall efficacy of antidepressants is well proven (Baghai, Volz, & Moller, 2006; M. Bauer, Whybrow, Angst, Versiani, & Moller, 2002a, 2002b; Bauer et al. 2007) and although recent meta-analysis question their true clinical usefulness (Kirsch et al. 2008), antidepressants constitute the only rigorously tested therapy against depression and their clinical utility is the only one solidly proven (Nutt & Malizia, 2008; Nutt & Sharpe, 2008).

Apart from antidepressants, other classes of psychotropic agents could be used to treat the constellation of symptoms that accompany depression as well as comorbid conditions. The most often used agents are anxiolytics, tranquillizers and sedatives. Usually benzodiazepines serve this role; however they induce tolerance and dependence. The alternative is pregabalin, which is officially labeled for the treatment of generalized anxiety, and atypical low-potency antipsychotics like quetiapine and olanzapine. Antipsychotics (either typical or atypical) are also prescribed when psychotic symptoms are present. Their side effects include extrapyramidal signs and symptoms, blurred vision, tardive dyskinesia, loss of libido and weight gain.

The therapeutic effect against depression, no matter whether the patient is under monotherapy or combination therapy takes at least two weeks to become evident. There is a number of theories that try to explain it, suggesting that the "down-regulation" of neurotransmitter receptors, or second (post-synaptic intracellular) messenger system alterations or the medium term modulation of neuronal plasticity might be the neurobiological mechanisms underlying the treatment effect. Unfortunately the therapeutic effect of antidepressants does not typically persist more than 36 months after discontinuation and the relapse rate is high and depends on the phase of the disease. It is reported than within the first year, if patients are left without treatment, around 50% of them will relapse if the remitted depressive episode was their first, around 75% if it was the second and maybe up to 90% if it was their third. Thus for those patients with a history of multiple episodes, relapse is almost certain and lifetime treatment necessary (Frank et al. 1990; Kupfer et al. 1992). International guidelines suggest at least 6 months of continuation antidepressant treatment after the full resolution of the index episode and if the patient is young and the episode was the first or second. For patients with history of episodes treatment should last at least 5 years if not indefinitely.

Regardless of the initial choice of antidepressant, at least 30% of patients will not respond to treatment sufficiently. Clinical impression and recent reports suggest that if there is no response after 3-4 weeks a change of treatment is necessary. Increasing the dosage is one reasonable option since it obviously affects clinical outcome but also increases the adverse effect burden. The maximum dosage recommended by regulatory authorities limits this option. Various alternative treatment strategies have been proposed for these non- or partially responsive depressions, and close work with the patient might produce favorable results. Research is in the way to identify genetic markers predictive of response or useful in the choice of treatment.

The options to treat patients that do not respond adequately to treatment with an antidepressant after 3-4 weeks include the following:

a. Increase the dosage to the highest tolerated or permitted by labeling.

b. Switch to another antidepressant within the same pharmacologic class. Research suggests that failure to tolerate or respond to one medication does not imply failure with other medications.

c. Switch to another agent from a different class of antidepressants gives a 30-50% chance of response (Rush et al. 2006; Thase et al. 2007).

d. Combining two antidepressants from different classes (McGrath et al. 2006)

e. Augmenting the antidepressant with other agents (e.g., lithium, psychostimulants or thyroid hormone)(Bauer et al. 2002a, 2002b)(Nierenberg et al. 2006))

f. Combining the antidepressant with a psychotherapeutic intervention (Thase et al. 2007).

Lithium is well investigated in placebo-controlled trials with positive results and is considered to be the best proven augmentation therapy (Bauer et al. 2002a, 2002b). Aripiprazole is also approved as adjunct therapy on antidepressants for the treatment refractory depression (Hellerstein et al. 2008). Other augmentation options include thyroid hormones (Nierenberg et al. 2006) and psychostimulants (amphetamine, methylphenidate or modafinil) but sometimes they seem to trigger manic or mixed episodes in patients suffering from bipolar disorder and this is particularly problematic to predict when the patient is pseudo-unipolar, that is a manic episode had not been present before. Anticonvulsants are used for patients with alcohol or substance abuse as well as for emotionally labile patients. These patients should not be given stimulants, as they exacerbate mood shifting and put the patient at a risk for abuse. A very frequent practice for refractory patients is the use of combination strategy which involves adding one or more additional antidepressants, usually from different classes. It is expected to use multiple and diverse neurochemical effects to boost treatment; however there is little data to support this practice.

Bipolar Disorder

The treatment of BD is complex and full of caveats for the clinician (Fountoulakis et al. 2005; Fountoulakis, Grunze, Panagiotidis, & Kaprinis, 2007; Fountoulakis, Magiria et al. 2007; Fountoulakis, Vieta et al. 2007). An important problem is that a specific and different treatment needs to be considered separately for manic, hypomanic, mixed and bipolar depression episodes. The first step demands all offending drugs (e.g., stimulants, illicit drugs, caffeine, and sedative-hypnotic agents) should gradually be discontinued, and circadian disruptions and sleep loss minimized.

Today several structured psychoeducational programs exist for patients with bipolar disorder. Hard data concerning the effectiveness of psychosocial interventions in BD are emerging and concern the prophylactic efficacy of cognitive therapy (Ball et al. 2006), family-focused therapy, interpersonal and social rhythm therapy, and cognitive behavior therapy (Miklowitz et al. 2007) and psychoeducation (Colom, Vieta, Martinez-Aran et al. 2003; Colom, Vieta, Reinares et al. 2003; Colom et al. 2004; Colom et al. 2005; Reinares et al. 2004; Scott, Colom, & Vieta, 2006). However, it seems that these modalities are effective only in a selective sample of patients with a rather more benign form of the illness.

The most well known are the following:

a. The behavioral family-management techniques developed by David J. Miklowitz and Michael J. Goldstein which include 21 one-hour sessions after the resolution of the acute phase. They promote family education, communication and problem-solving skills.

b. Monica R. Basco and A. John Rush developed a highly structured three-phase program targeting at educating the patient, teaching cognitive-behavioral skills for coping with symptoms and psychosocial stressors, improving compliance and monitoring the course of the illness.

c. The psychoeducational program developed by Eduar Vieta and Fransesc Colom has similar goals, is highly structured and lasts approximately one year after the resolution of the acute phase. It seems that patients at an earlier stage of the illness have a better prognosis after attending it.

d. Social rhythm interpersonal psychotherapy: This intervention integrates an interpersonal approach with an effort to stabilize daily activities, especially sleep, eating and working hours.

The biological therapy is the hallmark of bipolar disorder which is considered one of the two major psychotic mental disorders (the other being schizophrenia). Classically the treatment of bipolar illness includes the use of the so-called mood stabilizers (lithium and specific anticonvulsants), antipsychotics and antidepressants.

The first effective medication was lithium salts and for a long time they were considered to be a wonder-like drug both for the acute phase and the prophylaxis. However, it was soon abandoned because of cases of toxicity and was considered unsafe. The problem was that in the beginning it was not possible to monitor plasma levels. Latter lithium’s efficacy limitations were evident since half of patients do not respond adequately. Latter, anticonvulsants were proven to be efficacious as well and more recently atypical antipsychotics. The usefulness of antidepressants is somewhat controversial. Several papers with treatment guidelines for BD have been published until today, in an effort to code the way of treatment (Fountoulakis et al. 2005).

Lithium has a well established effectiveness against acute mania (Bowden et al. 1994; Bowden et al. 2005; Keck et al. 2007; Kushner, Khan, Lane, & Olson, 2006) but maybe not against acute depression (Young et al. 2008). The data are far stronger concerning the effectiveness of lithium during the maintainance phase (Bowden et al. 2000; Bowden et al. 2003; Calabrese et al. 2003; Calabrese et al. 2006; Goodwin et al. 2004; Kane et al. 1982). After its discontinuation the likelihood of relapse is very high (50% in the first 5 months and above 80% within the first 18 months). Drawbacks of lithium therapy include its narrow therapeutic index (recommended plasma level 0.8– 1.2 mmol/L), poor tolerability, especially at higher doses, and risk of "rebound mania" on withdrawal (Goodwin, 1994). Common side effects of lithium are tremor, polydipsia, polyuria, and in the long-term, hypothyroidism. However, in spite of these shortcomings, lithium still remains the gold standard of treatment and additionally it might have an antisuicidal effect (Baldessarini et al. 2006; Gonzalez-Pinto et al. 2006).

Of the anticonvulsants, only valproate, carbamazepine and lamotrigine possess data concerning the treatment of bipolar illness. Both valproate and carbamazepine are effective against acute mania (Bowden et al. 1994; Bowden et al. 2006; Pope, McElroy, Keck, & Hudson, 1991; Weisler, Kalali, & Ketter, 2004; Weisler et al. 2005; Weisler et al. 2006) but against acute bipolar depression valproate is effective (Davis, Bartolucci, & Petty, 2005; Ghaemi et al. 2007) while the data concerning carbamazepine are less robust (Ballenger & Post, 1980). The typical dosages for valproic acid are 750-2000 mg daily, with blood concentration 50-120 mg/mL. Rapid oral loading with divalproex using 15 to 20 mg/kg from day 1 of treatment, has been well tolerated and associated with a rapid onset of response. Blood concentrations above 45 mg/mL have also been associated with earlier response. The typical dosages for carbamazepine to treat mania are 600-1800 mg daily and correspond to blood concentrations of 4-12 mg/mL. But for neither agent blood concentrations predict response. An important problem is that after several weeks carbamazepine induces hepatic enzymes thus lowering its levels and requiring an upward dose titration. Lamotrigine seems not to be effective during either the acute manic (unpublished clinical trials) or the acute depressed phase (Goldsmith, Wagstaff, Ibbotson, & Perry, 2003). During the maintenance phase, data are negative for valproate (Bowden et al. 2000), and weak for carbamazepine (Okuma et al. 1981). On the contrary they are strong for lamotrigine but only concerning the prevention of depression (Bowden et al. 2003; Calabrese et al. 2000; Calabrese et al. 2003). The data concerning the other anticonvulsants are either negative (Kushner et al. 2006) or do not exist, although there are open studies and case reports including complicated cases (Oulis et al. 2007). Valproate is reported to possess a relatively high teratogenicity. Other side effects include weight gain and hair loss and maybe the induction of polycystic ovarian syndrome. A potentially life-threatening side-effect of carbamazepine may be the Steven-Johnson syndrome and related dermatologic effects. Lamotrigine has a moderately high incidence of rash, thus titration should be very slow.

All atypical antipsychotics seem to be effective against acute mania (Fountoulakis & Vieta, 2008) but only quetiapine and the olanzapine plus fluoxetine combination are considered to be effective and thus approved against acute bipolar depression (Calabrese et al. 2005; Thase et al. 2006; Tohen, Vieta et al. 2003). Aripiprazole and olanzapine have sufficient data concerning their efficacy during the maintainance phase (and approved) (Keck, Jr. et al. 2007; McQuade, Sanchez, Marcus, & al, 2004; Tohen et al. 2006), although aripiprazole prevented only manic episodes, while data on the efficacy of quetiapine during the maintenance phase have been recently announced and approved (Altamura, Salvadori, Madaro, Santini, & Mundo, 2003; Altamura et al. 2008). Typical antipsychotics (haloperidol, chlorpromazine, perphenazine) although seem to posses efficacy against acute mania (McIntyre, Brecher, Paulsson, Huizar, & Mullen, 2005; Shopsin, Gershon, Thompson, & Collins, 1975; Smulevich et al. 2005) they also seem to predispose patients to manifest dysphoria or depression (Tohen, Goldberg et al. 2003; Zarate & Tohen, 2004). Adverse effects of antipsychotics include extrapyramidal symptoms and signs, induction of diabetes mellitus and a metabolic syndrome, sedation, hyperprolactinemia and tardive dyskinesia.

Antidepressants should never be used as monotherapy but always together with a mood stabilizer or an atypical antipsychotic, because of the risk to induce the opposite pole, mixed episodes and rapid cycling. Adjunctive studies report that around 14% of bipolar depressed patients under both an antidepressant and a mood stabilizer switch to mania or hypomania (Post et al. 2001; Post et al. 2006). The meta-analysis suggests a higher switch rate for venlafaxine in comparison to SSRIs; however the studies included were randomized trials of adjunctive treatment, maybe including more refractory patients (Leverich et al. 2006). Fluoxetine has a proven efficacy against bipolar depression (Amsterdam et al. 1998; Amsterdam & Shults, 2005a, 2005b; Cohn, Collins, Ashbrook, & Wernicke, 1989) especially in the frame of the combination with olanzapine (E. B. Brown et al. 2006; Tohen, Vieta et al. 2003).

Since in real life the biggest proportion of BD patients do not do well on monotherapy, several combination therapies have been tested and several agents have been tested as an add-on therapeutic option (Fountoulakis & Vieta, 2008).

Other Treatment Modalities

a. Electroconvulsive therapy (ECT) (Daly et al. 2001; Sikdar, Kulhara, Avasthi, & Singh, 1994; Small et al. 1988) could serve as a useful option even in patients who have failed to respond to one or more medications or combined treatment although rigorous data are not available. It can be used both against acute mania and acute depression either unipolar or bipolar. It seems to be effective in both psychotic and nonpsychotic depression, and bilateral ECT is more effective than unilateral, but with more cognitive adverse effects. It is very useful for severely suicidal patients.

b. Transcranial magnetic stimulation (rTMS) (Dolberg, Dannon, Schreiber, & Grunhaus, 2002; Nahas, Kozel, Li, Anderson, & George, 2003; Saba et al. 2004) has shown both some antimanic and antidepressant effects at 20 Hz over the right but not left frontal cortex or at 1 Hz rTMS bifrontally, but the efficacy has not been solidly proven yet.

c. Light therapy is useful for the treatment of mood disorder with seasonal pattern, either as monotherapy or in combination with medication.

Combined Treatment

A significant percentage of mood patients are refractory to any monotherapy. Comorbidity and the successful treatment of the comorbid condition is one of the factors connected to treatment resistance (Sharan & Saxena, 1998). In this frame combination treatment is the only reasonable strategy, and it is important to embed the antidepressant therapy into a complex therapeutic approach with multiple modalities. However, relatively few studies have investigated its benefits, and in particular, the combination of psychotherapy with antidepressants does not always provide a solidly proven advantage (de Maat et al. 2008; Hegerl et al. 2004).

Psychoeducation and psychotherapy may ameliorate the social problems which appear as a consequence of the mood disorder and might improve compliance with mood-stabilizer agents. A formal approach could be that psychotherapy is used to increase adherence, improve the moral and solve interpersonal and social problems, while medications are used for symptom control. Psychotherapy might be added especially after a partial medication response but it is unclear when this should happen, since the evidence suggests that psychosocial and occupational improvements follow response. Thus, routine use of both treatments initially may not be necessary for psychosocial restoration.

Special Populations/Gender/Cultural Issues

Gender

Studies have shown that nearly all around the world, women have nearly double rates of depression than men although this is not well documented in non-industrialized cultures (Lloyd & Miller, 1997). The National Comorbidity Study reported that 6% of the females vs. 3.8% of males suffered from a current depressive episode and that 21.3% of women vs. 12.7% of men had a lifetime experience of a depressive episode (D. G. Blazer, Kessler, McGonagle, & Swartz, 1994). The rates for bipolar disorder are similar however, suggesting this difference concerns only unipolar depression. A second finding suggests that women with less social support and experiencing social stressors might be at the greatest risk to develop depression. However, there is no significant gender difference concerning the risk of recurrence, thus suggesting that gender is among the risk factors for initiating depressive symptoms but not among those determining the course and outcome. This higher risk for females is present around the age of 20s until the early 30s and that the rates of first onset before (childhood and adolescence) or after that age (middle age, elderly) are similar for both sexes (Nazroo, Edwards, & Brown, 1997; Philibert, Richards, Lynch, & Winokur, 1997).

It seems highly unlikely that there a single, sex-related factor which is responsible for the difference. Endocrine changes and differences were being the target of research without convincing results. The role the female reproductive system might play in mental health is still controversial. The fact that the gender difference is not obvious until puberty, and disappears after menopause, supports the idea that there is something specific connecting the female biology to mood disorders. A more advanced approach suggests that this biology is not a risk factor per se; on the contrary it could be responsible for an increased vulnerability to stressors, thus indirectly leading to depression, especially considering the second fact that women are more likely to experience stressful and even threatening life events and are at a higher risk of early sexual abuse and current spousal abuse (Finkelhor, Hotaling, Lewis, & Smith, 1990; Roesler & McKenzie, 1994). They also might use oral contraceptive use, and often experience mood disorders temporally related to their sexual identity (e.g., premenstrual or postpartum-onset mood disorders). Additionally, almost all societies have designated different, unequal roles for women.

On the other hand, since no conclusive data are available so far, it is necessary to consider the possibility that men and women share similar rates of depression, but they express depression in different ways and the resulting different rates is in reality a methodological artifact. In this case, it’s reasonable to suggest that different cognitive coping styles between men and women could be responsible for these results and maybe women are more likely to be diagnosed with depression because they seek professional help more often for their depressive symptoms and maybe because they are more sensitive to negative relationships (Phillips & Segal, 1969). It is believed that men might react to emotional distress by trying not to think about it, while women are more likely to ruminate over their problems (Nolen-Hoeksema & Girgus, 1994; Nolen-Hoeksema, Larson, & Grayson, 1999; Nolen-Hoeksema, Stice, Wade, & Bohon, 2007). In this frame, women are more likely to report depressive symptoms due to marital problems than men. This could at least partially be socio-culturally determined, or imposed, since it is reported that the depressed female students who reached out to their friends were met with concerned and nurturing reactions, while in contrasts, the depressed male students who did the same, faced social isolation and often direct rejection, even hostility (Hammen & Peters, 1978; Joiner, Alfano, & Metalsky, 1992). While married, divorced, and separated women were more likely to be depressed than men, widowed men were more likely to be depressed than women and unmarried men and women shared similar rates of depression (Radloff & Rae, 1979).

Another possibility is that in men, but not in women, alcohol abuse could mask an underlying depressive disorder an could account for the difference in the rates. This opinion derives from the observation that alcohol abuse and mood disorders are often inherited in the same family (Triffleman, Marmar, Delucchi, & Ronfeldt, 1995).

It should be noted, however, that the excess of females in mood disorders is accounted for solely by unipolar disorders (e.g., major depression, dysthymia); the bipolar disorders affect men and women equally.

Suicide

Today we know that suicide is a complex and multicausal behavior and demands a complex and sophisticated approach. Statistics point to a substantial decline of suicide rates throughout Europe, the US and Canada during the past two decades, and the major reason for that seems to be the better recognition of major depression as well as availability of treatment (Akiskal, Benazzi, Perugi, & Rihmer, 2005; Cipriani, Pretty, Hawton, & Geddes, 2005; Isometsa, Henriksson et al. 1994; Z Rihmer, Belso, & Kiss, 2002; Z. Rihmer & Akiskal, 2006). The understanding and preventing of suicide is one of the most challenging tasks for psychiatry today. It has been confirmed by several psychological autopsy studies that the majority of suicidal victims were suffering from a mood disorder, usually untreated major depression, with frequent comorbidity of anxiety and substance-use disorders (Badawi, Eaton, Myllyluoma, Weimer, & Gallo, 1999; Barraclough, Bunch, Nelson, & Sainsbury, 1974; Henriksson et al. 1993; Monkman, 1987; Rihmer et al. 2002; Rihmer, 2007). Around 60-80% of all suicide victims are suffering from depression while on the other hand, an estimated 15% of patients with severe major depression eventually die from suicide. The rate of attempted to completed suicide, is about 5 to 1 in patients with any mood disorder (Tondo, Isacsson, & Baldessarini, 2003).

Although many risk factors have been identified, most of them are not clinically useful. An important and useful risk factor is the presence of a depressive mixed state (3 or more simultaneously co-occurring hypomanic symptoms in patients with “unipolar depression”). This clinical picture overlaps to a great extent with agitated depression. Depressive mixed state as well as agitation substantially increase the risk of both attempted and committed suicide (Akiskal, Benazzi et al. 2005; Balazs et al. 2006; Isometsa, Henriksson et al. 1994; Rihmer & Akiskal, 2006; Rihmer, 2007). Other risk factors include family history of suicide, higher number of prior depressive episodes, comorbid anxiety, personality disorders and alcohol dependence, as well as sociodemographic and psycho-social factors such as younger age, being divorced or widowed, and experiencing adverse life-situations which are associated with increased suicidal ideation and higher prevalence of attempts (Balazs et al. 2006; Bernal et al. 2006; Henriksson et al. 1993; Rihmer et al. 2002; Z. Rihmer & Akiskal, 2006; Z. Rihmer, 2007). Although biological research has so far identified several biological correlates of suicide today there is no biological marker found yet to distinguish explicitly between suicidal and non suicidal depressives (Nordstrom et al. 1994; Samuelsson, Jokinen, Nordstrom, & Nordstrom, 2006).

An impressive fact is that in spite of frequent medical contact before committing suicide, only a small minority of victims had received appropriate treatment. This is particularly a problem in primary care, where most patients seek help (Henriksson et al. 1993; Isometsa, Aro, Henriksson, Heikkinen, & Lonnqvist, 1994; Luoma, Martin, & Pearson, 2002; Z. Rihmer, Barsi, Arato, & Demeter, 1990; Rihmer et al. 2002). Thus not only early identification of suicidal behavior is possible but also early intervention is possible and could make a difference. The patient should be put on a plan of regular psychiatric visits on an interval ranging from once to twice weekly. Latter visits could be planned on a month interval or even less frequently. The main factors determining frequency include the clinical picture, social and family support, history of adherence, insight into the illness and the risk and medication adverse effects. The therapist should have in mind that antidepressive agents are the only formally approved treatment for major depression (Akiskal, Benazzi et al. 2005; Z. Rihmer & Akiskal, 2006; Yerevanian, Koek, Feusner, Hwang, & Mintz, 2004) and there are no data supporting the effectiveness of any other approach (Fountoulakis, Gonda, Siamouli, & Rihmer, 2008). Also a marked anti-suicidal effect has been also reported with long-term lithium therapy in bipolar (manic-depressive) patients (J. Angst, Angst, Gerber-Werder, & Gamma, 2005; Cipriani et al. 2005; Rihmer & Akiskal, 2006). Recently, the U.S. Food and Drug Administration issued a warning concerning the use of antidepressants in children and adolescents and possibly in all age groups because of possible induction of suicidality (thinking and behavior but not completed suicide) by antidepressants in juvenile depressives (FDA, 2009). A similar warning is in place now concerning anticonvulsants. However, the impact of this warning might be robustly negative.

The warnings are based on data from RCTs but there is doubt whether the design of these studies permit these conclusions. A recent study reports that after the warning, (between 2003 and 2005) the SSRIs prescriptions for children and adolescents in the US and the Netherlands decreased by about 22% but simultaneously there was a 49% youth suicide rate increase in the Netherlands (between 2003 and 2005) and a 14% in the US (between 2003 and 2004) (Gibbons et al. 2007). It is highly possible the "natural" population of mood disorders patients does not respond to treatment this way. On the contrary it seems that proper and "aggressive" treatment of mental disorders and especially of major depression aiming at achieving full remission should always be the target and determines to a large extent whether suicidal behavior is expressed or not (Angst et al. 2005; Moller, 2006; Sondergard, Lopez, Andersen, & Kessing, 2007; Tiihonen et al. 2006). However, a caveat is that the most dangerous period for suicide in a patient is immediately after treatment has commenced, as antidepressants may reduce the symptoms of depression such as psychomotor retardation or lack of motivation before mood starts to improve. Although this appears to be a paradox, studies indicate the suicidal ideation is a relatively common component of the initial phases of improvement even with psychotherapy (Moller, 1992).

Substance Use Comorbidity

Substance use and abuse is an old problem which recently gained significant importance. A large variety of different substances could be related with use or abuse and consequently with substance-induced mood disorders (Schuckit et al. 1997; Winokur et al. 1998). They include various medications (e.g., anesthetics, anticholinergics, antidepressants, anticonvulsants, antibiotics, antihypertensives, corticosteroids, antiparkinson agents, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, and disulfiram), toxic agents (heavy metals, industrial solvents, household cleaning agents), or substances used routinely for recreational purposes (e.g., caffeine, nicotine). Almost all the substances are preferred because of their subjective effects which concern mainly the mood. Others are used for their calming or "therapeutic-like" effect (as self-treatment, e.g., alcohol, sedatives) while others for their stimulating, euphoric and augmenting effect (e.g., stimulants).

Substance use and abuse could happen in the frame of a pre-existing mood disorder or the use itself can be the cause of the disorder (because of the direct physiological effects, toxicosis, withdrawal or dependence). When the mood disorder is primary and pre-exists, substance use complicates both the clinical manifestations and the treatment, and might lead to poor prognosis. This is especially often during teenage and early adult years, and relates mainly to cyclothymia and probably represents attempts of self-medication for the mood liability. During the withdrawal period many substances including alcohol, opioids, and sedatives might induce persistent mood disturbance, insomnia and cognitive disorder leading to relapse of the abuse. These symptoms need to be distinguished from those of primary mental disorders, and this is often very difficult. The critical factor is the clinician's judgment that the mood disorder is caused by the substance or not. A double diagnosis is usually the only reasonable solution. However, the "self-medication" scenario with mood disorder being primary, or even the double diagnosis are unfortunately not the diagnostic priority of many therapists (especially in therapeutic communities) and consequently, the missing of the diagnosis of mood disorder deprives the patient from proper and effective treatment.

Alcohol use and abuse is very frequent especially for mood and anxiety patients. On the other hand, heavy alcohol consumption over a period of days results in a depressive state, which even when it is severe, it largely improves within days to weeks of abstinence. After several weeks, most alcoholic patients manifest residual low mood or mood swings resembling a cyclothymic or dysthymic disorder but they also tend to diminish and disappear with time. The presence of the dysthymic symptoms usually indicates the normal course of a withdrawal syndrome and not an independent mood disorder. Nicotine use and abuse is also very frequent usually in the form of cigarette smoking and withdrawal is manifested by changes in mood, anxiety and weight gain (average is 2 to 3 kg) which can persist even for months.

Amphetamine, cocaine, opioid, hallucinogen or inhalant - induced mood disorder can occur during intoxication or withdrawal. In general, for all this substances, intoxication is associated with manic or mixed mood features, whereas withdrawal is associated with depressive mood features. An induced mood disorder by any of them usually remits within a week or two (several weeks for opioids), except from panic episodes that develop during cocaine use which could persist for many months following cessation (Krystal, Price, Opsahl, Ricaurte, & Heninger, 1992; Weddington et al. 1990). An important outcome is suicide which is not an uncommon complication.

Pediatric

Although the core features of mood disorders are essentially the same across the life span, traditionally children and the elderly are considered somewhat separately because of the special features their phase of life includes and the way these features might influence the overall manifestation of mental disorders and their treatment. Additionally, an early age of onset of any disorder puts forward the question whether this determines a more severe and chronic disease and also poor response to treatment.

It seems that the developmental phase might influence the expression of certain mood symptoms and that’s why e.g., pervasive anhedonia or significant psychomotor retardation are rare among depressive children and auditory hallucinations and somatic complaints are seen more often in prepubertal children.

The incidence of mood disorders among children and adolescents is reported to increase during the last few decades. These reports are rather consistence and they also suggest there is a decrease of the age of onset of mood disorders. The general picture suggests that the prevalence of depression is around 0.3% for pre-school children, 0.4–3% for school aged children and 0.4–6.4% for adolescents; the prevalence of bipolar disorder is 0.2–0.4% in children and 1% in adolescents. Research suggests that 40-70% of children and adolescents with a mood disorder have also at least one comorbid psychiatric disorder. The risk factors as well as the etiopathogenesis for this age group are uncertain.

Concerning suicide and related behavior, the attempted suicide is 1% in children and 1.7–5.9% in adolescents, while the completed suicide rate ranges from nearly zero in children below the age of 10, to a peak of above 18/100,000 in boys 15-19 years old. The data suggest that among 15-19 year-olds, the suicide rates have quadrupled over the last four decades, and the reason for this is not known. Unfortunately, suicide is currently the fourth leading cause of death in children aged 10-15 years and the third leading cause of death among adolescents and young adults aged 15-25 years. The suicidal method is the most significant factor which determines whether the attempt will result in death. The great majority of attempts among children and adolescents have little lethal potential partially because of restricted access to lethal material and inadequate cognitive potential to plan a successful attempt. What is unique in this age group is suicide imitation and contagion. This means that the suicidal behavior increases in adolescents following exposure to well-publicized news stories of suicide or a film involving a teen suicide, but this seems to concern vulnerable individuals and not the age group as a whole (Brent et al. 1993; Cheng, Hawton, Lee, & Chen, 2007; Gould & Shaffer, 1986).

The etiopathogenesis of mood disorders in children and adolescents is not well understood. It is an age group which combines developmental vulnerability and high potency for neuroplastisity and compensation for any insults. It is generally believed that genetic factors play a significant role; however there are vague data in support of this and no clear conclusions can be made. Non-shared environmental factors might also play an important role (Pike & Plomin, 1996). At the cognitive level, the theoretical approach suggests the presence of cognitive distortions similar to those seen in adults but again data are inconsistent and scarce.

Traditionally there has been significant interest on the family interactions and their relationship to the development of depression, but the conditions are usually complicated and difficult to interpret. The most difficult problem is that when the family environment is problematic, then, there is a high probability of a genetic vulnerability in the family and sometimes in both parents. However, this does not exclude the possibility the environment to induce a kind of emotional vulnerability in the child by shaping the early experiences. Depressed parents may model negative cognitive styles and poor self-esteem, leading to a deficit of social problem-solving skills and in coping with stressful life events; marital conflict and lack of an adequate family support system especially when a mental illness of the parent(s) of an early onset, is recurrent, and disrupts parental functioning puts the child at a high risk for any mental disorder but especially for a mood disorder. In this frame, it is understandable why family conflict is the most frequent event adolescents report they experienced, before they manifest suicidal behavior. There are several studies suggesting that depressed children and adolescents might experience more stressful life events like interpersonal losses, problems in relationships, parental divorce, bereavement, physical abuse and suicide in the environment (Beautrais, Joyce, & Mulder, 1997; Gould, Shaffer, Fisher, & Garfinkel, 1998; Kaplan, Pelcovitz, Salzinger, Mandel, & Weiner, 1997; Williamson, Birmaher, Anderson, al-Shabbout, & Ryan, 1995).

The conclusion concerning the etiopathogenesis of mood disorders in children and adolescence is that genetics clearly plays at least a moderate role while both shared and non-shared environmental influences appear to be also important.

Clinically depression in this age group presents with the same core features manifested in adults. Some minor differences suggest the presence of irritable rather than depressed mood and failure to attain expected weight gain instead of weight loss. Among pre-school children often lack of smiling, apathy towards play, lack of involvement in all activities, physical complaints, and physical aggression while among school-aged children, deteriorating school performance, increased irritability, fighting, or argumentativeness and avoidance of peers may signal depression. Exacerbation of anxiety symptoms and school refusal are not uncommon among children who are depressed.

Switching from unipolar depression to bipolar disorder is significantly higher in children than it is in adults, and it reaches 32% within a 5 year period. Also, it is reported that in children, mania might present with a chronic instead of an episodic pattern, with mixed and rapid cycling features instead of classic manifestations and high comorbid mental disorders. These suggest that childhood-onset bipolar disorder is a more severe form of the illness, and relatively treatment resistant. The main disorders that should be differentially diagnosed are attention-deficit/hyperactivity disorder and disruptive behavior disorders (Geller & Luby, 1997).

The psychological treatment of children and adolescents with mood disorders are similar to those for adults. On the contrary there is a significant controversy concerning pharmacotherapy. Double-blind studies are missing and it seems that these age groups are particularly vulnerable for the induction of suicidality by antidepressants. Flouxetine, quetiapine and lithium are the better studied agents in terms of efficacy in these age groups (Andrade, Bhakta, & Singh, 2006; Azorin & Findling, 2007; Barzman, DelBello, Adler, Stanford, & Strakowski, 2006; Chang, 2008; DelBello et al. 2006; DelBello, Adler, Whitsel, Stanford, & Strakowski, 2007; Dudley, Hadzi-Pavlovic, Andrews, & Perich, 2008; Jensen, Buitelaar, Pandina, Binder, & Haas, 2007; Marchand, Wirth, & Simon, 2004; Tsapakis, Soldani, Tondo, & Baldessarini, 2008; Usala, Clavenna, Zuddas, & Bonati, 2008). ECT and TMS might be reasonable alternatives if initial therapeutic attempts fail (Morales, Henry, Nobler, Wassermann, & Lisanby, 2005).

Geriatric

A world wide trend is the increase in both the absolute numbers and percentage in the total population of the elderly. This of course leads to an increase in the numbers of geriatric psychiatric patients and a shift of the focus of health care services. At the same time, geriatric mental patients present with multiple challenges both at the diagnostic as well as the therapeutic level.

The prevalence of major depression is estimated to be 2% in the general population over 65 years of age (Blazer, Burchetti, Service, & al, 1991; Reynolds, 1992; Vaillant, Orav, Meyer, McCullough Vaillant, & Roston, 1996), with up to 15% having some kind of other mood disorder (Branconnierm et al. 1983) and 25-40% of patients in the general hospital setting having a sub-threshold depression (Rapp, Parisi, & Walsh, 1988). In residential homes, the accepted value for patients with MDD is approximately 12%, with an additional 30% manifesting a milder form of depressive-like symptomatology (Foster, Cataldo, & Boksay, 1991; Katz, Lesher, Kleban, Jethanandani, & Parmelee, 1989; Katz & Parmelee, 1994; NIH, 1992; Parmelee, Kleban, Lawton, & Katz, 1991; Weyerer, Hafner, Mann, Ames, & Graham, 1995).

The recognition of geriatric mood patients (with a late onset mood disorder) is poor and less than 50% of hospitalised patients with depression in general medical practice are referred to a psychiatrist, and less than 20% receive adequate treatment (Shah & De, 1998). The same time, geriatric patients with depression have up to 1.5-3 times higher morbidity (Parmelee, Kalz, & Lawton, 1992), with the lifetime risk of suicide being as high as 15%; almost 10% of them die annually (Murphy, 1994). The ratio of males to females with MDD remains stable across the age spectrum (PW Burvill, Hall, Stampfer, & Emmerson, 1989).

Late onset mood patients are less likely to have a positive family history for mood disorders compared to younger patients (Hopkinson, 1964; Mendlewicz, 1976) and are more likely to manifest structural changes of the CNS (Burvill et al. 1989; Jacoby & Levy, 1980; Rabins, Pearlson, Aylward, Kumar, & Dowell, 1991). Neuroimaging studies have reported a variety of morphological disturbances, which clearly differentiate late-life depression from depression of younger ages (Greenwald et al. 1996; Jakoby, Lewy, & Bird, 1980, 1981; Rabins et al. 1991; Sackheim, Prohonik, Moeller, & al., 1993; Steffens & Krishnan, 1998; Uradhyaya, Abou-Saleh, Wilson, Grime, & Critchley, 1990), clearly suggesting an association to an increased severity of subcortical vascular disease and greater impairment of cognitive performance (Salloway et al. 1996). More, major depression is more common and more severe in patients with vascular dementia (Ballard, Bannister, Solis, Oyebode, & Wilcock, 1996).

Various studies of depression in the elderly reported that mood is more often irritable than depressive (Monfort, 1995), and also several symptoms like loss of weight, feelings of guilt, suicidal ideation, melancholic features, hypochondriasis as well as associated symptoms of psychosis could be more frequent (Brown, Sweeney, Loutsch, Kocsis, & Frances, 1984; Lader, 1982; Lyness, Conwell, & Nelson, 1992; Musetti, Perugi, Soriani, Rossi, & Cassano, 1989; Nelson, Conwell, Kim, & Mazure, 1989). However, these findings vary across studies. Many of these patients manifest a type of behavior that can be characterized as "passive-aggressive" or "self-aggressive." They refuse to get up from bed, eat, wash themselves, or talk. Also, they often hide important information concerning severe somatic disease and in this way they let it go untreated.

Somatic symptoms are difficult to assess and, as a general rule, physicians should avoid assigning this symptomatology to an underlying mental disorder. It is highly likely the patient indeed suffers from a true "somatic" disorder even in cases the physician is unable to diagnose it (APA, 1994). On the other hand, it is clear that elderly depressives manifest more somatoform symptomatology, in comparison to younger depressives. In this frame, the concept of Masked Depression (Modai, Bleich, & Gygielman, 1982) used to be popular in the past, but today it is not accepted by either classification system although it is accepted that the onset of health concerns in old age is more likely to be either realistic or to reflect a mood disorder (APA, 1994). Percentages of comorbidity between depression and physical illness vary from 6% to 45% (Kitchell, Barnes, Veith, & al. 1982; Kok, Heeren, Hooijer, & al., 1995). The large discrepancy reflects the difficulty in the application of operationalized criteria for the diagnosis of depression in patients with general health problems. Greater overall severity of medical illness, cognitive impairment, physical disability and symptoms of pain or other somatic complaints seem to be a more important predictor of depression than specific medical diagnoses (Williamson & Schulz, 1992).

About 38-58% (Alexopoulos, 1991) of the elderly suffering from major depression also fulfill criteria for an anxiety disorder while many authors have suggested that the presence of anxiety in the elderly should be considered as a sign of depression, even in cases, which lack true depressive symptomatology (Collins, Katona, & Orrell, 1994).

In elderly individuals there is an increased possibility of the co-existence of depression and dementia, or some other type of "organic" decline of cognitive disorder. The syndrome of "pseudodementia" has also been described (Kiloh, 1961). This term refers to the manifestation of dementia symptomatology, which in fact is due to depression and disappears after antidepressant therapy. It is also described the emergence of late onset bipolarity in the frame of an ongoing dementing pathology (Akiskal & Pinto, 1999; Akiskal & Benazzi, 2005; Ng et al. 2007)

Suicide constitutes an important health problem for the elderly. Elderly men are at a higher risk for completing suicide than elderly women. The co-existence of a serious somatic disease, like renal failure or cancer, represents a major risk factor for a well-planned suicide attempt (Heikkinen & Lonnqvist, 1995). Other risk factors include loneliness and social isolation, usually as a consequence of bereavement. The failure to follow medical advice in serious general medical conditions could be considered to be a form of "passive suicide." On the other hand, "rational" suicide plans are not common even in severely ill patients. There is a possibility of acute-onset suicidal plans (after an acute incidence concerning general health e.g., stroke or heart attack) (Kishi, Robinson, & Kosier, 1996).

The pharmacotherapy of late-onset mood disorder includes the cautious use of antidepressants including amitriptyline, imipramine, nortriptyline and all the SSRIs which are most widely prescribed antidepressants among the geriatric population, because of their favorable side-effect profile, relative safety in overdose, ease of use and smaller dosage adjustment makes them first-line choices. Also venlafaxine, mirtazapine, and bupropion could be useful.

For bipolar cases, lithium and anticonvulsants are useful although they are not well studied in elderly patients (Fountoulakis et al. 2003). It is mostly used in cases of refractory depression for the augmentation of antidepressant therapy. Antipsychotics, especially second generation ones could be used although there is a warning for a higher mortality because of their use in the elderly. ECT is another option with many studies reporting better outcomes in older than in younger patients. However, by far the most troubling side effect of ECT, especially in the elderly, is cognitive impairment.

Psychotherapy is also an option (Gerson, Belin, Kaufman, Mintz, & Jarvik, 1999; Gum & Arean, 2004). The presence and severity of medical illnesses, physical disability, cognitive impairment and psychomotor retardation make psychotherapeutic intervention difficult and affect its efficacy and success. The form of psychotherapy should be adjusted to the patient’s personality, behavior patterns as well as his/her cultural and educational level. Behavioral therapy, cognitive-behavioral therapy and problem-solving therapy have been extensively studied for their effectiveness in the treatment of depression in elderly. Fewer studies have been carried out for the efficacy of interpersonal psychotherapy. Non-standardized psychotherapies such as, psychodynamic psychotherapy and reminiscence therapy, are also proposed as appropriate treatments for geriatric depression.

The combination of pharmacological and psychological treatments is associated with higher improvement rates than pharmacotherapy alone and considered more effective than either treatment alone in preventing recurrence of depression (Bartels et al. 2002). In long-term therapies, the addition of psychotherapy promotes adherence to treatment (Pampallona, Bollini, Tibaldi, Kupelnick, & Munizza, 2004).

Eventually however, most studies support the opinion that geriatric depression carries a poorer prognosis than depression in younger patients. However, many authors attribute this, to factors like failure to make an early diagnosis and improper or insufficient treatment. For patients with geriatric depression, the prognosis is more dependent on physical handicap or illness and lack of social support, however further research on this issue is needed. Thus, the effective prevention of late-life depression requires attention to maintaining the community infrastructure and support.

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