ANTIDEPRESSANT AGENTS

1. Poznan University of Medical Sciences, Chair and Department of Pharmacology ANTIDEPRESSANT AGENTS Katarzyna Manikowska, PhD

2. I. INTRODUCTION Mood disorders (also known as affective disorders) are syndromes consisting of signs and symptoms that are clearly abnormal for the individual experiencing them. Episodes tend to occur in periodic fashion, with varying degrees of residual symptoms between them. Mood disorders are distinguished from other major mental illnesses, such as schizophrenia, on the basis of the presence or absence of specific clusters of symptoms and the longitudinal course of the illness. Many patients fulfill the diagnostic criteria both for a mood disorder and for other psychiatric disorders, such as anxiety disorders, substance-use disorders, and personality disorders.

3. PATHOGENESIS No single physiologic mechanism for mood disorders has been identified. Nonetheless, considerable evidence suggests the involvement of: • several neurotransmitter systems, especially the monoamines (noradrenergic, serotoninergic, and perhaps dopaminergic pathways) • abnormalities in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes.

4. PATHOGENESIS Noradrenergic systems are involved in mood, arousal, appetite, reward, and drives; Serotoninergic systems are involved in mood, sleep, and impulsivity; Dopaminergic systems are important for pleasure and reward, as well as for psychomotor activity. These monoamine systems all arise in cell groups in the brain stem and are widely dispersed throughout the forebrain. Chronic hyperactivity of the HPA axis is arguably the biologic finding that is most often reported in severe and psychotic depression, and it normalizes with clinical recovery. The pathogenesis of depression in relation to biogenic amines and the HPA axis is an area of intensive research.

5. Biogenic Amine Hypotheses • It has been posited that mood disorders are caused by relative deficiencies in the availability of the norepinephrine (NE) or the serotonin (5-hydroxytryptamine [5-HT]) within the central nervous system, perhaps involving alterations in receptor function, signal transduction, or both. • Findings related to the adrenergic system include alterations in cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG), which is the major metabolite of NE, and alterations in NE availability.

6. Several subtypes of adrenergic receptors have also been studied, and several alterations have been noted. These include an increase: • in the binding of alpha2-adrenergic receptors in platelets; • a blunting of the growth hormone response to clonidine (an alpha2 receptor agonist); • in the density of beta-adrenergic receptors in postmortem brains of suicide victims. Furthermore, a multitude of studies have documented downregulation of beta-adrenergic receptors after long-term treatment with antidepressants—particularly monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs)—and after electroconvulsive therapy (ECT).

7. During recent decades, close scrutiny of the serotoninergic system in the brain has revealed alterations in various measures of serotoninergic neural activity and integrity, as well as 5-HT receptor alterations, in patients with depression. The CSF concentration of the serotonin metabolite 5-hydoxyindoleacetic acid (5-HIAA) has repeatedly been reported to be decreased in depressed patients, especially those who are suicidal. Alterations in 5-HT transporters and receptors have also been studied; such alterations include: • an increase in the density of postsynaptic 5-HT2 receptors • a decrease in the density of 5-HT transporter sites. The response to fenfluramine, an agent that releases 5-HT from the presynaptic terminal, is diminished in patients with depression.

8. Neuroendocrine and Neuropeptide Hypotheses (continued) Several measures of HPA-axis hyperactivity have been reported in depressed patients. These include: • increased concentrations of CRF in CSF, • a blunted ACTH response to exogenous CRF administration, • decreased CRF receptor density in the frontal cortex of suicide victims, • pituitary and adrenal gland enlargement, • increased ACTH and cortisol production, • nonsuppression of plasma cortisol levels after the administration of dexamethasone (the dexamethasone suppression test).

9. Neuroendocrine and Neuropeptide Hypotheses (continued) Hypothyroidism has long been known to be frequently associated with a markedly depressed mood. The HPT axis involves the secretion of thyrotropin-releasing hormone (TRH) by thehypothalamus, which stimulates the anterior pituitary gland to release thyroid-stimulating hormone (TSH). This in turn stimulates the secretion of thyroxine and triiodothyronine from the thyroid gland. A multitude of alterations in the activity of the HPT axis have been observed in patients with depression. Such abnormalities include: • increased TRH concentrations in CSF, • blunted or exaggerated TSH response to TRH stimulation, decreased nocturnal plasma TSH concentrations, • the presence of antimicrosomal thyroid or antithyroglobulin antibodies.

10. Neuroendocrine and Neuropeptide Hypotheses (continued) Mood disorders have also been reported to be associated with alterations in the activity of the growth hormone axis and the hypothalamic-pituitary-gonadal (HPG) axis. The burgeoning field of psychoneuroimmunology has provided evidence of abnormal immune function, including alterations in cytokine secretion, in depressed patients.

11. Other Hypotheses Neuroimaging studies (e.g. PET) show clear abnormalities in the activity of several circuits in depressed patients, including: • decreased metabolism in the frontal cortex • increased metabolism in certain limbic areas. Sleep abnormalities in depression include: • increased time to sleep (initial insomnia), • earlier onset of rapid eye movement (REM) sleep (decreasedREM latency), • reduction in sleep stages 3 and 4, • changes in phasic REM activity, • disturbances in the continuity of sleep, • early-morning awakenings.

12. Diagnostic criteria Standarized criteria are used to separate normal depression caused by disappointment or having a bad day from the disorders of mood called AFFECTIVE DISORDERS, which are actually syndromes.

13. Simplified clinical description of an ICD-10 depressive episode*  Core symptoms Depressed, irritable or apathetic mood Loss of interest and enjoyment Reduced energy Other common symptoms Reduced concentration and attention Reduced self-esteem and self-confidence Ideas of guilt and unworthiness Bleak and pessimistic view of the future Ideas or acts of self-harm or suicide Disturbed sleep Diminished appetite General Severity graded according to symptom burden and associated impairment Duration of at least 2 weeks  *Based on the ICD-10 Classification of Mental and Behavioral Disorders, ICD-10, International Statistical Classification of Diseases and Related Health Problems, 1989 Revision. Geneva; World Health Organization, 1992,

14. Laboratory Tests At present, there are no validated routine laboratory tests to diagnose depression. The dexamethasone suppression test, a measure of HPA axis activity, is not sufficiently sensitive or specific for diagnosis or for monitoring response. Instead, diagnosis is made according to the descriptive clinical criteria set forth in the DSM-IV.

15. Laboratory Tests(continued) Several laboratory tests should be ordered to help exclude other explanations for the depressive symptoms. Medical conditions that may be physiologically associated with depression include: • endocrinopathies (e.g., hypothyroidism, hyperthyroidism, parathyroid disorders, Cushing syndrome, or Addison disease), • neurologic disorders (e.g., stroke, subcortical dementias, neurosyphilis, multiple sclerosis, Parkinson disease, neurosarcoidosis, CNS vasculitis, or HIV-associated CNS pathology), • other disorders (e.g., vitamin deficiencies, anemia, hypoglycemia or hyperglycemia, hypoxia, end-stage renal disease, lupus, or occult malignancies such as pancreatic cancer).

17. Tricyclic antidepressants (TCAs ) TCAs act at several transporters and receptors, but their antidepressant effect is likely produced by the blocking of the reuptake of NE, 5-HT, or both at their presynaptic terminals, increasing the availability of these neurotransmitters. The TCAs can be subdivided into the tertiaryamines, which are dual 5-HT/NE reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine) and the secondary amines, which are primarily NE reuptake inhibitors (e.g., desipramine, nortriptyline).

18. Tricyclic antidepressants The use of TCAs is limited by their unfavorable side-effect profile (largely resulting from their anticholinergic, antiadrenergic, and antihistaminic properties); these side effects include: • blurred vision, dry mouth, tachycardia, constipation, urinary retention, cognitive dysfunction, postural hypotension, dizziness, sedation, weight gain, and sexual dysfunction. TCAs also have a narrow therapeutic index and are lethal in overdose (resulting in part from an inhibition of sodium channels that causes a slowing of cardiac conduction and potentially fatal arrhythmias). Efficient use of TCAs is also limited by the need to slowly titrate the dose and the need for therapeutic drug monitoring to avoid toxicity.

19. Tricyclic antidepressantsDose and Dosage Forms, and Side Effects

20. Selective Serotonine Reuptake Inhibitors (SSRI) The first SSRI, fluoxetine, was introduced in the United States in 1988. There are currently six SSRIs approved by the Food and Drug Administration: fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram. These agents all share the property of blocking the reuptake of 5-HT, but there is increasing evidence that they produce other effects as well. The SSRIs are effective in treating depression and many primary anxiety disorders. They offer several important advantages over the older medications. They require minimal dose titration, and the starting dose is sometimes an effective and even optimal dose. Perhaps most importantly, these medications are safe in overdose.

21. The SSRIs have a relatively mild side-effect burden. Sexual side effects of these medications (i.e., delayed ejaculation, anorgasmia,decreased libido) are being increasingly recognized and studied and are one of the leading causes of discontinuance or noncompliance.

22. Selective serotoninereuptake inhibitors (SSRI) Dose and Dosage Forms, and Side Effects

23. Newer agents are believed to act on serotoninergic and noradrenergic pathways in the brain by a variety of mechanisms, including dual 5-HT/NE reuptake blockade (venlafaxine), 5-HT2 blockade (trazodone, nefazodone, mirtazapine), and alpha2 autoreceptor blockade (mirtazapine). Bupropion was originally thought to act as a dopamine and NE reuptake inhibitor, but its mechanism of action remains somewhat obscure. In addition to having FDA approval for depression, bupropion is approved for smoking cessation (partial agonist nACh-receptor).

24. Antidepressants: Chemical Structures, Dose and Dosage Forms, and Side Effects

25. Actions of Monoamine Oxidase à Two MAO isoenzymes are known à MAO-B is the predominant enzyme in many parts of brain à MAO-A - is present in NA-ergic and 5-HTS neurons (locus ceruleus) - is the main enzyme in peripheral tissues - is the target for drugs useful in treating depression

26. CLASSICAL (non-selective) MAO-INHIB PHENELZINE TRANYLCYPROMINE MAO-A inhibition in the brain produces the therapeutic effects of these drugs; MAO-A inhibition in the gut wall and liver important consequences. They are rarely used because their use is complicated by side effects (including hypotension), lethality in overdose, and lack of simplicity in dosing.

27. Patients treated with MAOIs must follow a specific tyramine-free diet because of the potential for a pharmacodynamic interaction with tyramine that can result in a hypertensive crisis. • Drugs that have been reported to interact with MAOIs include carbamazepine, cyclobenzaprine, dextromethorphan, fenfluramine, certain hypoglycemics, L-tryptophan, meperidine, selective serotonin reuptake inhibitors (SSRIs), stimulants, sympathomimetics, and TCAs. • Nonetheless, the MAOIs appear to be more effective than other antidepressants in the treatment of atypical depression, though their use is usually limited to psychiatrists who have experience with these agents. • MAOIs are also often effective in patients with depression that is refractory to treatment with other antidepressants.

28. CLASSICAL (non-selective) MAO-INHIBDose and Dosage Forms, and Side Effects

29. Reversible inhibitors of monoamine oxidase A MOCLOBEMIDE Moclobemide is a selective reversible inhibitor of MOA-A (RIMA). This isoenzyme is the target for the antidepressant action of classical MAOIs. If tyramine is absorbed from the gut, MAO-B is able to degrade it and the food reaction seen with classical MAOIs is very unlikely to occur. Also since the action of moclobemide on MAO-A is reversible, high concentrations of tyramine will displace the drug from the enzyme, further facilitating tyramine degradation. If moclobemide is taken after meals, then inhibition of MOA-A in the gut during absorption of tyramine will be minimised, providing further protection. Enzyme inhibition by moclobemide lasts than 24 h after a single dose.

30. MOCLOBEMIDE Pharmacokinetics • Oral absorption is good but there is substantial first-pass metabolism, partially to an active metabolite. • Extensive hepatic metabolism gives a short half-life. Unwanted effects • Unwanted effects are: CNC stimulation can produce sleep disturbance or agitation nausea dizziness, headache. Drug interactions • Inhibition of cytochrome P450 activity in the liver by cimetidine substantially reduces the metabolism of moclobemide and smaller starting doses are recommended in this situation.