Introduction To Mood Disorders And Limitations Of Current Treatments

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Bipolar disorder and unipolar depression are classified as mood disorders. They are common, severe, and chronic illnesses. Depression is typified by a depressed mood, anhedonia (inability to experience pleasure), feelings of worthlessness or excessive guilt, impaired sleep (either insomnia or hyper-somnia), cognitive and concentration deficits, psychomotor changes, recurrent thoughts of death or suicide, and a variety of neurovegetative symptoms. In bipolar disorder, patients typically alternate (albeit not in a one-to-one manner) between episodes of depression (mostly indistinguishable from unipolar depression) and episodes of mania, which is characterized by a heightened mood, hyperaroused state, racing thoughts, increased speed and volume of speech, quicker thought, brisker physical and mental activity levels, inflated self-esteem, grandiosity, increased energy (with a corresponding decreased need for sleep), irritability, impaired judgment, heightened sexuality, and sometimes frank psychotic symptoms such as hallucinations and delusions. Bipolar Disorder is further classified into bipolar I or II, based on clinical presentation. Bipolar I disorder is defined by a history of one or more manic episodes. Bipolar II is defined by a history of one or more hypomanic episodes and at least one depressive episode. In hypomania, a less severe form of mania, the changes noted for the description of mania above are generally observed but are more moderate and do not result in hospitalization. Both diseases commonly first appear in young adulthood, though early and late onset of both diseases is not uncommon. They are often comorbid with other conditions, most commonly anxiety disorders with depression and drug and alcohol abuse with bipolar disorder.

The courses of both depression, bipolar I, or bipolar II are characterized by episodes of mood changes, separated by periods of euthymia (normal mood). However, their episodic courses with intervening periods of recovery belie the severe impact of these diseases. The accumulating effect of recurring bouts of depression and/or mania leads to an increased rate of marital and family breakdown, unemployment, impaired career progress, and consequent financial difficulties.

Both diseases are pervasive, being associated with increased morbidity and mortality. This arises not only from a rate of suicide approaching 15% for both disorders, but additionally the existence of significant medical comorbidities, often limited social and economic functioning, and poor inter-episode recovery: aspects that are increasingly being recognized (see [1] and accompanying special issue of Biological Psychiatry). For example, the World Health Organization ranks diseases not solely based on fatal outcomes, but additionally nonfatal outcomes in a measurement referred to as a disability-adjusted life year (DALY) [2]. By this metric they found in 1999 that worldwide, depression ranked the fifth worst and bipolar disorder ranked twentieth. Further DALYs from depression and bipolar disorder diseases were higher in developed countries such as the United States. The World Health Organization projects that by the year 2020 depression will be the second cause of DALYs worldwide (only to cardiovascular disease) [2].

While once thought to have primarily environmental origins, uncontrover-sial evidence now exists that genetic and other biological factors play a central role in the pathogenesis of mood disorders. Epidemiological evidence consisting of studies involving families, siblings, and twins is supportive of a strong genetic diathesis. For instance, while bipolar disorder affects about 1% of the world's population overall, monozygotic twins and first-degree relatives are afflicted about 60% and 7% of the time, respectively [3,4]. Major depression is even more common than bipolar disorder in the overall population (15% lifetime risk); however, first-degree relatives of probands develop the disease at three times this rate [5,6]. Heritability estimates for bipolar disorder and depression are approximately 80% and 33%, respectively [5,7,8] (compare to type 2 diabetes at 26% [9]). While bipolar disorder is equally prevalent in men and women, depression is at least twice as common in women. Genetic linkage and association studies are beginning to show promise but are hindered by phenotypic and genetic heterogeneity, in addition to the likely complex contribution of epigenetic and environmental factors [10-12]. However, the true pathology of these diseases has proved elusive. Past theories have centered on dysregulation of monoaminergic (serotonin and norad-renergic) signaling pathways, which are involved in the actions of some medications (vide infra) and alteration of which can precipitate mood episodes (e.g., reserpine precipitating depression and amphetamine or l-dopa induced mania). Updated theories take into account changes in neuronal plasticity predisposing neuron and glial cells of the brain to impaired function

There exist varied treatments for mood disorders. Medications useful for treating mania and depression fall into two general classes; these are mood stabilizing medications and antidepressants, respectively. Lithium was the first treatment specifically for bipolar disorder, and it has proven efficacy in the treatment of both bipolar mania and depression [14]. Additional classes of medications that have been successful in double-blind studies for the treatment of bipolar disorder include select anticonvulsants (valproate, carbam-azepine, and lamotrigine), and antipsychotics. The antipsychotic class includes the atypicals (e.g., clozapine, olanzapine, riperidone) and typicals (haloperi-dol, chlorpromazine), and while they appear most efficacious in the treatment of mania, some studies suggest efficacy in the treatment of depression as well [15,16].

Unipolar and bipolar depression is generally treated with antidepres-sants belonging to medication classes that act by increasing synaptic levels of monoamines (generally serotonin and/or norepinephrine). These medications include tricyclics (e.g., desipramine, imipramine), selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine), and monoamine oxidase inhibitors (MAOIs; phenelzine, tranylcypromine). Refractory depression, and also mania, may be treated with electroconvulsive therapy (ECT).

However, despite these options there exists an urgent need for novel medications for the treatment of both bipolar disorder and depression. Current compounds often do not bring about full remission, and if they do, it is after a minimum of many weeks, if not months of treatment. Additionally they often lack the complete ability to prevent breakthrough episodes, lack specificity because of disease heterogeneity, or commonly have undesirable side effects even in the best efficacy scenarios (e.g., sexual side effects with SSRIs [17]). The development of novel therapeutics for severe mood disorders has been hindered by both limited knowledge regarding the underlying neurobiol-ogy of the disorders and limited evidence regarding how the most useful medications actually exert their beneficial effects [18-20]. Without a firm understanding of these issues, it will be impossible to develop truly novel therapeutics for the treatment of mood disorders. Thus ongoing studies to elucidate both the complex etiologies of these disorders and the relevant mechanism of action (both direct and downstream) of current drugs hold vast promise for major advances.

As mentioned, almost all current antidepressants (tricyclics, SSRIs, MAOIs, etc.) appear to initially target neural circuits that rely upon the neuro-transmitters serotonin and norepinephrine. In contrast, the initial relevant target(s) of mood-stabilizing agents (e.g., lithium and valproate) are not established, but there is evidence for direct inhibition of particular intracel-lular enzyme (s) (see [18] for review). Importantly, a great deal of experimental evidence suggests that the downstream therapeutic targets of both antidepressants and mood stabilizers are critical intracellular signaling pathways [10]. Thus a simple increase in the intrasynaptic levels of a "deficient neurotransmitter" likely does not explain the true mechanisms of action of antidepressants. Indeed, this seems unlikely since the therapeutic effects are only observed after weeks of administration. This observation, coupled with a number of negative and spurious findings, has led to the conclusion that increasing intrasynaptic levels of serotonin and/or norepinephrine is simply an initiating event that induces a cascade of signaling and gene expression changes in critical neuronal circuits, effects that are ultimately responsible for the medications' therapeutic effects.

It is unfortunate that most recent pharmaceutical efforts to develop "novel" medications for the treatment of bipolar disorder have relied primarily on testing medications initially envisioned and approved for other indications (most generally antipsychotic and antiepileptic drugs for the treatment of bipolar disorder) in hope that they may have efficacy. An alternative approach is to develop medications specifically for bipolar disorder based on direct and indirect targets of known medications [18].

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