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Introduction

The primary clinical manifestations of major depression are significant depression of mood and impairment of function. Some features of depressive disorders overlap those of the anxiety disorders, including panic-agoraphobia syndrome, severe phobias, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Extremes of mood also may be associated with psychosis, as manifested by disordered or delusional thinking and perceptions that often are congruent with the predominant mood. Conversely, secondary changes in mood may be associated with psychotic disorders. This overlap of disorders can lead to errors in diagnosis and suboptimal treatment. Mood and anxiety disorders are the most common mental illnesses, each affecting up to 10% of the general population at some time in their lives.

Clinical depression must be distinguished from normal grief, sadness, disappointment, and the dysphoria or demoralization often associated with medical illness. The condition is underdiagnosed and frequently undertreated .Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, lack of pleasure, self-deprecation, and variable agitation or hostility. Physical changes also occur, particularly in severe, vital, or “melancholic” depression. These include insomnia or hypersomnia; altered eating patterns, with anorexia and weight loss or sometimes overeating; decreased energy and libido; and disruption of the normal circadian and ultradian rhythms of activity, body temperature, and many endocrine functions. Almost 10% to 15% of individuals with severe clinical depression, and up to 25% of those with bipolar disorder display suicidal behaviour at some time. Depressed patients usually respond to antidepressant drugs, or, in severe or treatment-resistant cases, to electroconvulsive therapy (ECT). This method remains the most rapid and effective treatment for severe acute depression and sometimes is life-saving for acutely suicidal patients. Efficacy of other forms of biological treatment of depression (e.g., magnetic stimulation of the brain, or electrical stimulation of the vagus nerve) has not been well established. The decision to treat with an antidepressant is guided by the presenting clinical syndrome, its severity, and by the patient’s personal and family history.

The major disorders of mood or affect include the syndromes of major depression (formerly termed melancholia) and bipolar disorder (formerly termed manic-depressive disorder). The lifetime prevalence of bipolar disorder is 1% to 2% for type I (with mania). It is about twice that rate if cases of recurrent depression with milder upswings of mood (hypomania) are included (type II bipolar disorder). Lifetime risk for major depression is considerably higher, at 5% to 10%, and approximately twice the risk in women than in men. These disorders commonly include disordered autonomic functioning (e.g., altered rhythms of activity, sleep, and appetite) and behaviour, as well as persistent abnormalities of mood. These disorders are associated with increased risk of self-harm or suicide as well as increased mortality from stress-sensitive general medical conditions, medical complications of comorbid abuse of alcohol or illicit drugs, or from accidents. Bipolar disorder is marked by a high likelihood of recurrences of severe depression and manic excitement, often with psychotic features.

The less pervasive psychiatric disorders include conditions formerly termed psychoneuroses, which currently are viewed as anxiety-associated disorders. The ability to comprehend reality is retained, but suffering and disability sometimes are severe. Anxiety disorders may be acute and transient, or more commonly, recurrent or persistent. Their symptoms may include mood changes (fear, panic, or dysphoria) or limited abnormalities of thought (obsessions, irrational fears, or phobias) or of behaviour (avoidance, rituals or compulsions, pseudoneurological or “hysterical” conversion signs, or fixation on imagined or exaggerated physical symptoms). In such disorders drugs can have beneficial effects, particularly by modifying associated anxiety and depression to facilitate a more comprehensive program of treatment and rehabilitation. Antidepressants and sedative-antianxiety agents are commonly used to treat anxiety disorder.

Antidepressants:

Most antidepressants exert important actions on the metabolism of monoamine neurotransmitters and their receptors, particularly norepinephrine and serotonin.

History; Monoamine Oxidase Inhibitor: In 1951 isoniazid and its isopropyl derivative, iproniazid, were developed for the treatment of tuberculosis. Iproniazid, a hydrazine derivative, was observed to have mood-elevating effects in patients with tuberculosis, but owing to hepatotoxicity was abandoned for this use. In 1952 Zeller and co-workers found that iproniazid, in contrast to isoniazid, inhibited monoamine oxidase (MAO). Following investigations by Kline and by Crane in the mid-1950s, iproniazid (MARSILID) was used to treat depressed patients; historically, it was the first antidepressant to be used clinically .Two other hydrazine-derivative inhibitors of MAO, phenelzine (the structural analogy of phenethylamine, an endogenous amine) and isocarboxazid, subsequently were introduced into clinical practice. Tranylcypromine, structurally related to amphetamine, was the first MAO inhibitor unrelated to hydrazine to be discovered and brought to the market. The development of reversible, selective MAO inhibitors with potentially broad applications (e.g., selegiline [eldepryl] for Parkinson’s disease) was stimulated by the understanding that the early MAO inhibitors result in irreversible and nonselective blockade of both MAO-A and MAO-B, which were responsible for the metabolic breakdown of dopamine, norepinephrine, and serotonin in neuronal tissues. Three other MAO inhibitors that are used for purposes unrelated to MAO inhibition are furazolidone (FUROXONE, an anti-infective); procarbazine (MATULANE; N-methylhydrazine, indicated for the treatment of Hodgkin’s disease); and linezolid (ZYVOX, an antibiotic used for serious infections).

Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors: Hafliger and Schindler in the late 1940s synthesized a series of more than 40 iminodibenzyl derivatives for possible use as antihistamines, sedatives, analgesics, and ant Parkinsonism drugs. One of these was imipramine, a dibenzazepine compound, which differs from the phenothiazines by replacement of the sulphur with an ethylene bridge to produce a seven-membered central ring analogous to the benzazepine antipsychotic agents. Following screening in animals, a few compounds, including imipramine, were selected for therapeutic trial on the basis of sedative or hypnotic properties. During clinical investigation of these putative phenothiazine analogues, fortuitously found that unlike the phenothiazines, imipramine was relatively ineffective in quieting agitated psychotic patients, but it had a remarkable effect on depressed patients. Since then, indisputable evidence of its effectiveness in major depression has accumulated.

Older tricyclic antidepressants with a tertiary-amine side chain (including amitriptyline, doxepin, and imipramine) block neuronal uptake of both serotonin and norepinephrine, whereas clomipramine is relatively selective against serotonin. Following this lead, even more selective serotonin reuptake inhibitors were developed in the early 1970s, arising from observations by Carlsson that antihistamines, including chlorpheniramine and diphenhydramine inhibited the transport of serotonin or norepinephrine. Chemical modifications led to the earliest selective serotonin reuptake inhibitor, zimelidine, soon followed by development of fluoxetine and fluvoxamine; although first to market, zimelidine was withdrawn due to an association with febrile illness and Guillain-Barre ascending paralysis. Thus, fluoxetine and fluvoxamine were the first widely used selective serotonin reuptake inhibitors (often abbreviated as SSRIs or SRIs). Development of these agents was paralleled by the identification of compounds with selectivity for norepinephrine reuptake, along with others effective against both serotonin and norepinephrine reuptake  again with potential for applications beyond depression and/or anxiety (e.g., atomoxetine).

By: Ammarah Khan