Endogenous Depression

In this condition, the patient experiences profound misery (beyond the observer's empathy) and feelings of severe guilt because of imaginary misconduct. The drive to act or move is inhibited. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpitations, loss of libido, impotence, etc.). Although the patient may have suicidal thoughts, psychomotor retardation prevents suicidal impulses from being carried out. In A, endogenous depression is illustrated by the layers of somber colors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced.

Therapeutic agents fall into two groups:

• Thymoleptics, possessing a pronounced ability to re-elevate depressed mood e.g., the tricyclic anti-depressants;

• Thymeretics, having a predominant activating effect on psychomotor drive, e g., monoamine oxidase inhibitors.

It would be wrong to administer drive-enhancing drugs, such as amphetamines, to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomo-tor inhibition (A), the danger of suicide increases.

Tricyclic antidepressants (TCA; prototype: imipramine) have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibitors (SSRI; prototype: fluoxetine).

The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics (p. 237). The side chain nitrogen is predominantly proto-nated at physiological pH.

The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal re-uptake of norepinephrine (p. 82) and serotonin (p. 116) is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, a-adrenocep-tors, and certain 5-HT and hista-mine(H1) receptors are blocked. Interference with the dopamine system is relatively minor.

How interference with these transmitter/modulator substances translates into an antidepressant effect is still hypothetical. The clinical effect emerges only after prolonged intake, i.e., 2-3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adaptive processes (such as downregulation of cortical serotonin and p-adrenocep-tors) are ultimately responsible. In healthy subjects, the TCAs do not improve mood (no euphoria).

Apart from the antidepressant effect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differentiated clinical use (p. 233), based upon the divergent patterns of interference with amine transmitters/modulators. Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated.

In contrast, desipramine produces psychomotor activation. Imipramine

occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipra-mine). Likewise, the desmethyl derivative of amitriptyline (nortriptyline) is less dampening.

In nondepressive patients whose complaints are of predominantly psy-chogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary "psychosomatic uncoupling." In this connection, clinical use as "co-analgesics" (p. 194) may be noted.

The side effects of tricyclic antide-pressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances. These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropine-like effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision.

Changes in adrenergic function are complex. Inhibition of neuronal cate-cholamine reuptake gives rise to superimposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of a1-receptors may lead to orthostatic hypotension.

Due to their cationic amphiphilic nature, the TCA exert membrane-stabilizing effects that can lead to disturbances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite.

Maprotiline, a tetracyclic compound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasyn-aptic concentrations of norepinephrine by blocking presynaptic a2-receptors, rather than reuptake. Moreover, it has less pronounced atropine-like activity.

Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is considered comparable to that of established antidepressants. Added advantages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse effects include: overarousal, insomnia, tremor, akathisia, anxiety, and disturbances of sexual function.

Moclobemide is a new representative of the group of MAO inhibitors. Inhibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels. A psychomotor stimulant thymeretic action is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irreversible inhibition of the two isozymes MAOa and MAOB. Therefore, presystem-ic elimination in the liver of biogenic amines, such as tyramine, which are ingested in food (e.g., aged cheese and Chianti), will be impaired. To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonse-lective MAO inhibitors calls for stringent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAOA and does so in a reversible manner.

Foods For Depression And Sleeplessness
A. Antidepressants: activity profiles
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