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Mood Disorders

Psychiatry - Classification & Disorders















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

pathogenesis
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 effi-cacy 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 psy-chotherapy 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 de-sipramine. 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 nore-pinephrine 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 reboxe-tine 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 benzodi-azepines 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 monother-apy 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 neurotransmit-ter 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 antide-pressant 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 intergrates 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 con-cerning 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.

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