Depression reserpine-induced

In humans, the antidepressant activity of NMDA receptor antagonists has not been evaluated extensively (Skohiick 1999). In animal models of depression, NMDA receptor antagonists have been reported to exert positive effects in most studies (Trullas 1997). This concerns mainly the forced swim test (Maj 1992 Moryl et al. 1993 PrzegaUnski et al. 1997) and stress-induced anhe-donia (Papp and Moryl 1994). Amantadine but not memantine was effective against reserpine-induced hypothermia (Moryl et al. 1993). In the forced swim test, both amino-adamantanes produced specific antidepressive-like activity (Moryl et al. 1993). 

It is also clear in retrospect that the reserpine-induced state was a state of dopamine blockade, characterised by sedation and inactivity, rather than a valid model of depression (Mendels Frazer 1974). Whether it commonly caused a true depressive state in humans has also been disputed. One review suggested that it did so in 6% of cases, but mostly in people who had a previous history of depression (Goodwin Bunney, Jr. 1971). The only controlled study of reserpine on mood found no true cases of depression, but several patients were noted to show signs of excessive tranquillisation or pseudodepression (Bernstein Kaufman 1960). 

The common adverse CNS effects for reserpine include drowsiness, fatigue, or lethargy. Mental depression is one of the most serious potential adverse effects for reserpine, which may be severe enough to require hospitalization or result in suicide attempts. Reserpine-induced depression may persist for several months after the drug is discontinued. 

A -Phenyldihydroindoles, in which there is also a structural relation to type (80-88), are the antidepressants amedalin (104) and daledalin (105). Clinical effectiveness was ascribed to both [271-273], but (104) gave scrotal and urination discomfort [272]. Compound (105) was as effective in depression as amitriptyline (5) but caused headache in 6 of 38 patients studied [273]. The pharmacological profile of (104) showed potent antagonism of reserpine induced hypothermia and tetrabenazine-induced sedation in rats. In dogs, a potentiation of NA pressor response was obtained by 1 mg kg p.o., which can be attributed to a neuronal uptake inhibiting effect of (104) [271,274]. In their series, (104) and (105) were the most potent in potentiation of adrenergic mechanisms [274]. 

Several diphenylmethane derivatives had antidepressive activity. Tbfenacin (13) was we11-tolerated and effective in patients with various kinds of depression. Like imipramine, some aminopropenes 1 reversed reserpine-induced hypothermia in mice. The (-)-isomer of caused clinical antidepressive actions, but these were accompanied by unwanted side effects. ... 

Two diethylpropion analogues (VIII) and (IX) have been described. The thiophene derivative (VIIl) and related amino modifications were claimed to have anorexigenic activity comparable to amphetamine with much less CNS stimulation. A chloro-substituted derivative (IX) [SKF-709h8, FWH-h9h) was reported to be one-fifth as potent as diethyl-propion in decreasing food intake in dogs it produced less motor stimulation in the mouse than d-amphetamine, reversed and prevented reserpine induced depression. In the anesthetized cat, a biphasic blood pressure response was observed.22 A clinical trial of (IX), at daily doses of 75-150 mg, revealed effects similar to those obtained with diethylpropion.23 A clinical study designed to demonstrate the effect of continuous versus intermittent administration of diethyl-prop ion was shown to favor continuous administration.2A A related... 

But that was only one half of the logic behind the chemical-imbalance theory. The other half came from studies of reserpine, a drug that was extracted from Rauvolfia serpentina or the Indian snakeroot plant, which had historically been used to treat snakebite, hypertension, insomnia and insanity. In studies of animals, reserpine was reported to induce sedation and to decrease brain levels of norepinephrine, serotonin and dopamine. Clinical reports indicated that some people became severely depressed when taking reserpine.14 Putting these two findings together, it seemed likely that reserpine made people depressed because it decreased neurotransmitter levels. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

The primary limiting effect of reserpine is depression. Depletion of central monoamines is believed to be the mechanism for this effect (Heninger et al. 1996 Charney 1998). The depression may occur in a gradual and insidious manner, and the causal association between the drug and depression may be missed (Oates 1996). Rauwolfia alkaloids are contraindicated in anyone with a history of depression, and careful vigilance is required to ensure that they do not induce depression in otherwise normal individuals. Additional side effects are sedation and difficulty with concentration and performing complex mental tasks. 

The most troublesome untoward effects of treatment with reserpine involve the CNS. Sedation and depression are the most common, although nightmares and thoughts of suicide also occur. Reserpine treatment, therefore, is contraindicated in patients with a history of severe depression. The occasional report of re-serpine-induced extrapyramidal symptoms, which are similar to those seen in patients with Parkinson s disease, is believed to be a result of dopamine depletion from neurons in the CNS. 

Reserpine at doses 0.25 mg May induce depression, impotence, sedation, and orthostatic hypotension. Low... 

In the unanesthetized dog, reserpine selectively depresses the sympathetic centers and induces facilitation of the parasympathetic centers in the diencephalon. The latter effect accounts for the bradycardia, miosis, aggravation of bronchial asthma, renal and biliary colic, and ulcerative colitis observed in some patients receiving the drug. 

It potentiates (already in low doses) the excitement syndrome induced by DOPA and simultaneously annihilates the depression caused by reserpine. In man, 74 seems to be useful in the treatment of psychoses and schizophrenia. 

Two of these studies reported that the antidepressant was superior for patients with "retarded" depression, whereas the neuroleptic was superior for anxious or neurotic patients (Hollister et al. 1967 Raskin et al. 1970). This is readily understandable, given what we know of the drug-induced effects of neuroleptics. Their deactivation effects are likely to compound psychomotor retardation and reduce agitation and anxiety. Reserpine, the drug that was believed to induce a depressive state, was found to be clearly superior to placebo for the treatment of depression in an early trial conducted at the Maudsley hospital in London (Davies Shepherd 1955). 

Reserpine was originally used for the treatment of hypertension and the depression which was frequently observed during reserpine therapy suggested that the alkaloid might have psychotherapeutic potentiality. In fact, the root of Rauwoljia serpentina, from which reserpine is prepared, had been used in Asia centuries ago for the treatment of manic states. In psychiati ically normal hypertensive patients, the depression induced by reserpine occasionally led to suicide and its use as a hypotensive drug had to be discontinued. Although severe depression occurred much less frequently during the... 

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