Psychopharmacology 3e Chapter 18 Summary

Affective Disorders: Antidepressants and Mood Stabilizers


Characteristics of Affective Disorders

Animal Models of Affective Disorders

  • Affective disorders, including major depression and bipolar disorder, are chronic disorders that recur in episodes over the life span. Symptoms are listed in Table 18.1.
  • The incidence of depression is approximately 15% to 20% of the population at any one time. Depression is twice as common in women and is highly comorbid with anxiety and alcohol abuse.
  • Bipolar disorder constitutes episodes of depression alternating with mania and occurs in about 1% of the population.
  • On the basis of twin studies and adoption studies, genetic contribution to the occurrence of major depression is estimated at 45%, and family history is the strongest predictor of vulnerability. Genetic contribution to bipolar disorder is significantly greater than that for depression.
  • Depression is associated with abnormalities of HPA axis function: high plasma ACTH and cortisol, hypersecretion of CRF, flat circadian rhythm of cortisol, and failure of dexamethasone-induced negative feedback.
  • In depression, altered sleep architecture is seen in the following conditions: onset insomnia, reduced slow-wave sleep, early onset of REM sleep, more frequent and longer REM episodes early in the night, and more vigorous eye movement during REM.
  • Individuals with mania sleep very little without loss of energy. In symptom-free patients, sleep deprivation initiates a manic episode. Because many rhythms are irregular, research into the CLOCK gene has increased.
  • Modeling complex psychiatric disorders poses multiple challenges, and each model focuses on one or a few symptoms. Each varies in face, predictive, and construct validity.
  • Exposing rodents to sleep deprivation and creating mutant mice with genes that affect the biological clock and circadian cycling are two means used to produce models of mania in rodents.

Neurochemical Basis of Mood Disorders

Neurobiological Models of Depression

  • The monoamine hypothesis was based on pharmacological evidence showing that depression is associated with low levels of monoamines, whereas mania coincides with excess monoamine activity.
  • Modifications of the hypothesis were needed to explain the discrepancy in time between the rapid increase in monoamines by antidepressant drugs and the slow onset of clinical effects over several weeks.
  • A role for 5-HT in depression is suggested by the following: (1) lower 5-HIAA occurs in depressed individuals, (2) knockout mice show some behaviors analogous to human depression, (3) depletion of tryptophan causes depressed mood in patients in remission, (4) a polymorphism of the SERT gene is associated with depression, and (5) increased postsynaptic 5-HT2 receptors are found in patients postmortem.
  • Chronic antidepressant treatment causes the down-regulation of 5-HT autoreceptors, which increases synaptic 5-HT and subsequent intracellular changes leading to neurogenesis and synaptic remodeling. The effects of fluoxetine on autoreceptor down-regulation and depression may depend on several factors, including pretreatment 5-HT function and the nature of the environment. The electrophysiological response to 5-HT is enhanced by chronic antidepressant treatment.
  • In depressed patients, chronic antidepressants increase NE turnover, which leads to down-regulation of β-adrenergic receptors and α2-autoreceptors.
  • Inhibiting the synthesis of 5-HT causes relapse in patients treated with serotonin reuptake inhibitors, but not in those treated with adrenergic antidepressants. Likewise, inhibiting NE synthesis produces relapse in patients treated with NE reuptake inhibitors, but not in those treated with serotonergic agents.
  • Prolonged hypersecretion of CRF, ACTH, and glucocorticoids damages dendritic branching and spines in the hippocampus and PFC. It also reduces neurogenesis in the hippocampus, which further diminishes the negative feedback on HPA axis function. Chronic antidepressants reverse these effects.
  • ICV CRF elicits stress-related behavior and hormone response and signs of depression in rodents. A clinical trial of a CRF antagonist improved depression and anxiety scores in patients.
  • The neurotrophic hypothesis suggests that stress hormones that reduce BDNF may cause neuronal damage, and antidepressants may prevent it by elevating BDNF. Intrahippocampal BDNF has antidepressant action.
  • Preventing hippocampal cell proliferation prevents antidepressant-induced neurogenesis and behavioral effects.
  • Chronic antidepressants up-regulate the cAMP cascade, leading to increased phosphorylated CREB and subsequent expression of BDNF. Enhancing the cAMP cascade by inhibiting phosphodiesterase produced antidepressant effects in some patients.
  • Evidence for BDNF in the etiology of depression includes the following: (1) BDNF is low in the hippocampus and the PFC of depressed patients postmortem, (2) a BDNF gene polymorphism may be associated with mood disorders, and (3) modifying BDNF gene expression in mice leads to depressive behaviors.

Therapies for Affective Disorders

  • Antidepressants of all classes reduce symptoms in about two-thirds of individuals after 4 to 6 weeks of treatment. Total remission of symptoms occurs less often. Continued treatment prevents relapse.
  • MAOIs elevate brain levels of monoamines by preventing their destruction in the presynaptic terminal by MAO and subsequently altering receptor number and intracellular signaling.
  • The most common side effects of MAOIs include changes in blood pressure, sleep disturbances, and weight gain. More serious side effects are associated with enhanced response to sympathomimetics, hypertensive crisis following elevation of tyramine levels, and drug interactions due to liver enzyme inhibition.
  • Tricyclic antidepressants block reuptake of NE or 5-HT or both, and this increases synaptic levels and produces subsequent compensatory changes in receptors and intracellular signaling.
  • Side effects of TCAs include sedation, anticholinergic effects, and potentially dangerous cardiovascular effects.
  • Second-generation antidepressants, including the SSRIs, are not more effective or more rapid in onset but are safer.
  • Side effects of SSRIs are due to enhanced 5-HT function at multiple 5-HT receptors and include sexual dysfunction. Potentially fatal serotonin syndrome occurs when SSRIs are combined with other serotonergic drugs. Physical dependence occurs in 60% of cases.
  • Mirtazapine enhances NE and 5-HT function by blocking α2-autoreceptors and heteroreceptors on 5-HT cells. It also blocks selective 5-HT receptors to reduce side effects.
  • Third-generation agents comprise CRF receptor antagonists, enhancers of the cAMP intracellular cascade, agomelatine, ketamine, galanin agonists, tianeptine, and AMPA agonists. Multiple potential mechanisms may explain ketamine’s rapid onset of antidepressant effects.
  • The ability of physical exercise to relieve depression may depend on its ability to increase neurogenesis and dendritic resculpturing.
  • Lithium carbonate reduces manic episodes without causing depression and reduces bipolar cycling. It is more effective than alternatives in reducing suicide rates.
  • Side effects of lithium are relatively mild, but toxic effects at the highest doses lead to seizures, coma, and death. The therapeutic index is very small, so frequent monitoring of blood levels is needed.
  • Lithium and other antimanic drugs modulate several intracellular signaling pathways, including the GSK-3 pathway, and neurotrophic factors.
  • The anticonvulsant valproate is as effective as lithium and has different side effects but is teratogenic, so its use in women of childbearing age is limited.
  • Carbamazepine has a time course and effectiveness similar to those of lithium with different side effects, some of which are liver toxicity and blood diseases. Induction of several cytochrome enzymes causes significant drug interactions.