Chapter 30 Treatment of Affective Disorders

Abbreviations
DA	Dopamine
5-HT	Serotonin
MAO	Monoamine oxidase
MAOI	Monoamine oxidase inhibitor
NE	Norepinephrine
SNRI	Serotonin/norepinephrine reuptake inhibitor
SSRI	Serotonin selective reuptake inhibitor
TCA	Tricyclic antidepressant

Therapeutic Overview

Depression is a heterogeneous disorder that involves bodily functions, moods, and thoughts and is characterized by feelings of sadness, anxiety, guilt, and worthlessness; disturbances in sleep and appetite; fatigue and loss of interest in daily activities; and difficulties in concentration. In addition, individuals with depression are often obsessed with suicidal ideations. Symptoms of depression can last for weeks, months, or years, and depression is a major cause of morbidity and mortality. In any given year, 9.5% of the population (approximately 18.8 million adults in the United States) suffers from a depressive illness, and depression is a factor in more than 30,000 suicides per year in the United States, making it one of the most widespread of all life-threatening disorders. Although depression can affect any age, the current mean age of onset is 25 to 35 years. Of particular concern is that the rate of depression and suicide among children, adolescents, and the elderly is increasing at an alarming pace and often goes unrecognized.

Depression is a symptom of many different illnesses. It may arise as a result of substance abuse (alcohol, steroids, cocaine, etc.), a medical illness (pancreatic carcinoma, hypothyroidism, etc.), or a major life stress event. However, it may also arise from unknown causes.

Three of the most important psychiatric illnesses that present with depressive symptoms are major depression, dysthymia, and bipolar depression. Major depression (also referred to as unipolar depression) may be totally disabling (interfering with work, sleeping, and eating); episodes may occur several times during a lifetime and may progress to psychosis. Dysthymia is less severe and involves long-term chronic symptoms that do not disable but keep a person from functioning at his or her highest level. Finally, bipolar disorder (manic-depressive disease) is a syndrome in which there are cycling mood

changes characterized by severe highs and gut-wrenching lows, which may worsen to a psychotic state. In addition, depression is often associated with comorbid anxiety disorders.

Major depression, dysthymia, and the depression associated with anxiety disorders are treated with compounds classified as antidepressants. These compounds fall into three broad categories:

• The amine reuptake inhibitors, which include the tricyclic antidepressants (TCAs), the serotonin selective reuptake inhibitors (SSRIs), and the serotonin/norepinephrine reuptake inhibitors (SNRIs).

• The atypical antidepressant drugs, which represent a heterogeneous group of compounds.

• The monoamine oxidase inhibitors (MAOIs).

Although their specific mechanisms of action differ, these drugs all share the ability to increase monoaminergic neurotransmission in the brain, primarily increasing the activities of pathways using serotonin (5-HT) and norepinephrine (NE) and possibly dopamine (DA) as neurotransmitters.

Although the molecular and cellular etiology of depression remains unknown, it is generally accepted that depression involves impaired monoaminergic neurotransmission, leading to alterations in the expression of specific genes. This is supported by studies demonstrating that antidepressants increase the expression of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) and brain-derived neurotrophic factor (BNDF), both of which are critical for maintaining normal cell structure in limbic regions of the brain that are targets for monoaminergic projections. In addition, postmortem and imaging studies have demonstrated neuronal loss and shrinkage in the prefrontal cortex and hippocampus in depressed patients, some of which could be reversed by antidepressants.

Within the past several years, as evidence of adult neurogenesis has become increasingly clear, the idea has emerged that depression may be caused by impaired neurogenesis in adult hippocampus. Studies have demonstrated that new neurons can proliferate from progenitor cells in the hippocampus, a process impaired by stress and stress hormones such as the glucocorticoids and enhanced by antidepressants. Furthermore it has been shown that neurogenesis is required for antidepressants to exert their behavioral effects in laboratory animals. Thus impaired monoaminergic transmission in specific brain regions may lead to a decreased expression of transcription or growth factors required for maintaining neurogenesis and perhaps increasing dendritic branching, resulting in depression.

In contrast to unipolar depression, bipolar disorder is characterized by depressive cycles with manic episodes, interspersed with periods of normal mood. The characteristics of the depressive phase resemble those of unipolar depression, whereas the manic phase manifests as increased psychomotor activity and grandiosity, feelings of euphoria, poor judgment and recklessness, extreme irritability, and symptoms sometimes resembling psychotic behavior. Bipolar disorder affects 2 million people in the United States, often begins in adolescence or early adulthood, and may persist for life. Evidence suggests a role for genetic factors, because the concordance rate in identical twins is 61% to 75%. However, the disorder cannot be attributed to a single major gene, suggesting multifactorial inheritance.

The treatment of bipolar disorder has changed over the past decade. Lithium has been the mainstay of treatment for many years, particularly for control of the manic phase. However, the anticonvulsants lamotrigine, valproic acid, and carbamazepine have been frequently used as well (see Chapter 34), especially in cases in which the bipolar disorder was characterized by rapid cycling. Recently, the atypical antipsychotic drugs aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone were approved as monotherapy for bipolar disorder (see Chapter 29). Antidepressants may also be warranted to treat the depressive phase of the illness.

The pharmacology of the antipsychotics is discussed in Chapter 29 and that of the anticonvulsants in Chapter 34. Therapeutic actions related to the antidepressants and lithium are summarized in the Therapeutic Overview Box.

Mechanisms of Action

The antidepressants may be generally classified according to their mechanisms of action as amine reuptake inhibitors, MAOIs, and mixed-action atypical drugs—the latter representing a heterogeneous group that includes compounds often referred to as second- or third-generation antidepressants.

Amine Reuptake Inhibitors and Atypical Antidepressants

The TCAs were the first group of antidepressants developed in the 1950s, and the prototypical compound imipramine

Therapeutic Overview
Antidepressants
Prolong the action of biogenic amines at the synapse by inhibiting amine reuptake, increasing amine release or decreasing amine catabolism
Enhance neurogenesis and dendritic branching in the adult hippocampus
Lithium
Interferes with receptor-activated phosphatidylinositol turnover; blocks the conversion of inositol phosphate to free inositol
Antagonizes 5-HT_1A and 5-HT_1B autoreceptors, alleviating feedback inhibition of 5-HT release
Enhances glutamate reuptake system, clearing glutamate from the synapse

was the first agent demonstrated to have antidepressant efficacy. The TCAs have a three-ring structure with a side chain containing a tertiary or secondary amine attached to the central ring, resembling the phenothiazine antipsychotics (Fig. 30-1). The tertiary amines include imipramine, amitriptyline, clomipramine, and doxepin; the secondary amines include desipramine and nortriptyline.

FIGURE 30–1 Structures of prototypical antidepressants.

The TCAs block the reuptake of NE, 5-HT, or both into noradrenergic and/or serotonergic nerve terminals, respectively, by specific interactions with plasma membrane transporters (Fig. 30-2). As a consequence of this inhibition, the actions of NE and 5-HT released from these neurons are not rapidly terminated, resulting in a prolonged stimulation of NE receptors, 5-HT receptors, or both. The TCAs do not affect the reuptake of DA by dopaminergic nerve terminals, and their selectivity for NE versus 5-HT transporters differs among the different compounds (Table 30-1).

FIGURE 30–2 A noradrenergic and serotonergic synapse and sites at which antidepressants may exert their actions. TCAs, SSRIs, and some atypical antidepressants inhibit the reuptake transporter for NE, 5-HT, or both. Monoamine oxidase, which is targeted by MAO inhibitors, is localized at the outer mitochondrial membrane.

TABLE 30–1 Relative Selectivity of Antidepressants for Amine Reuptake

In addition to inhibiting NE and 5-HT reuptake, the TCAs also block muscarinic cholinergic receptors, α₁ adrenergic receptors, and histamine H₁ receptors. These actions underlie many of the side effects of these compounds.

The SSRIs and SNRIs also inhibit the reuptake of biogenic amines, and as their name implies, the SSRIs have the highest affinity for 5-HT transporters, whereas the SNRIs have high affinity for 5-HT transporters and moderate affinity for NE transporters. It is important to note, however, that specificity and selectivity are always dose-related such that the SSRIs sertraline and paroxetine inhibit both NE and DA reuptake at the upper end of their dose ranges (see Table 30-1). Similarly, it is also important to keep in mind that the classification of newly developed compounds is based on their affinity for specific transporters, whereas that of the TCAs is based on chemical structure. Thus, although clomipramine is classified chemically as a TCA, its ability and selectivity to inhibit 5-HT and NE reuptake matches that of the SSRI paroxetine. Likewise, the selectivity of the TCAs imipramine and amitriptyline resemble that of the SNRI duloxetine. Thus, at times, classification schemes may be misleading.

As mentioned, the atypical compounds are a very heterogeneous group of drugs. Among these, maprotiline and nefazodone are relatively selective inhibitors of NE reuptake (see Table 30-1). Trazodone is a weak inhibitor of 5-HT reuptake, bupropion weakly inhibits DA reuptake, and mirtazapine appears devoid of activity at any reuptake transporter.

Trazodone, nefazodone, mirtazapine, and several TCAs have also been shown to block 5-HT_2A receptors with a high potency, and these drugs are at least fivefold more potent in vitro as antagonists of this receptor than as inhibitors of 5-HT reuptake. These receptors are widely distributed throughout the brain at regions containing 5-HT nerve terminals, and their stimulation produces depolarization. Interestingly, chronic antagonism of these receptors leads to their paradoxical down regulation, although the role of this mechanism in mediating the antidepressant actions of these compounds remains to be elucidated.

Mirtazapine also blocks α₂ adrenergic receptors on noradrenergic and serotonergic nerve terminals and on noradrenergic dendrites (Fig. 30-3). Stimulation of α₂ autoreceptors on noradrenergic neurons decreases NE release, whereas stimulation of α₂ heteroreceptors on serotonergic neurons inhibits 5-HT release. In addition, stimulation of α₁ adrenergic receptors on serotonergic cell bodies and dendrites increases their firing rate. Thus mirtazapine, by inhibiting α₂ autoreceptors, enhances noradrenergic cell firing and the release of NE, which activates α₁ adrenergic receptors to increase 5-HT release while concurrently blocking α₂ heteroreceptors, further facilitating the release of 5-HT.