Reserpine depression with

In a series of analogues (53) showed a pronounced antidepressant profile. It counteracted reserpine (depression in mice and emesis in pigeons) and potentiated the action of amphetamine. The position of the alkanoyl residue seemed to be very specific. Small variations of the propionyl moiety abolished the antidepressant activity and (in some cases) gave other effects e.g. depressive with Et CHOH- and hypotensive with EtSOi- [156]. Compound (53) was well tolerated and showed no particularly adverse effect in humans in a 4-wk study at 40-80 mg daily. Ginical studies in patients have been started [157]. 

Sensitivity to Convulsant Treatments - PCPA facilitates convulsions el-Icited by hyperbaric oxygen,39 pentylenetetrazolelectroconvulsive shock, Oa,41 audiogenic convulsant stimuli,42 flurothyl43 and withdrawal from barbiturates.44 a substantial older literature, originating with the work of Chen et al45 on reserpine, deals with the role of biogenic amines in experimental seizures. The preponderance of these reports indicate that stimulation of 5-HT receptor activity decreases seizure susceptibility, and that depression of 5-HT receptor activity exerts the opposite effect. 

VMATs are irreversibly inhibited by the potent antihypertensive drug reserpine. The depressive effects of reserpine helped to formulate the original monoamine hypothesis of affective disorders. Reseipine also appears to interact with the transporters near the site of substrate recognition. Tetrabenazine, which is used in treatment of movement disorders, inhibits VMAT2 much more potently than VMAT1, consistent with the less hypotensive action of this agent. 

A link between the central monoamines, 5-hydroxytryptamine (5-HT) and noradrenaline, and depression was forged some 40 years ago and arose from clinical experience with the drugs, reserpine and iproniazid. At that time, reserpine was used as an... 

Other Agents Reserpine No recommendations at this time Mental depression May be used in resistant hypertension when combined with a thiazide... 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

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. 

In comparison with more modem antihypertensives reserpine causes unpleasant side-effects, such as sedation, depression and various effects reflecting a dominant parasympathetic system (nasal congestion, diarrhea and exacerbation of peptic ulcers). Reserpine should be considered as an antihypertensive of second choice, although in certain countries it is still used because of its low price. 

The chief use of reserpine is in the treatment of mild to moderate hypertension. As with other sympathetic depressant drugs, tolerance to the antihypertensive effects of reserpine can occur, owing to a compensatory increase in blood volume that frequently accompanies decreased peripheral vascular resistance. Reserpine, therefore, should be used in conjunction with a diuretic. 

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 and iproniazid research led to the monoamine hypothesis of depression. This hypothesis proposed that a reduction in the monoamine neurotransmitters caused depression. As described in the sidebar on pages 82-83, only a small number of neurons use serotonin as a neurotransmitter, but these cells project to widespread regions of the brain. The same holds true for norepinephrine and dopamine. Although not widely used in the nervous system, these neurotransmitters are apparently involved in networks of neurons that greatly influence a person s mood. Synaptic transmission between neurons in other areas of the brain—such as neurons that process visual information, for instance—often carry specific messages, such as the presence of an object at a certain point in the person s visual field. In contrast, the monoamine neurotransmitters underlie information processing of a more general nature, some of which correlates with mood. 

This phenomenon is one of the pillars of the biogenic amine hypothesis of depression (see Suicide later in this chapter). An intriguing finding with reserpine is that those susceptible to a depressive syndrome while on this agent also have an increased likelihood of a personal or family history of MDD, in comparison with those who are not susceptible. This finding suggests an interaction between a constitutional predisposition and the biochemical effects of this drug. Because depression is a... 

Jensen K. Depression in patients treated with reserpine for arterial hypertension. Acta Psychiatr Neuroi Scand 1959 34 195-204. 

High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression occasionally, these occur even in patients receiving low doses (0.25 mg/d). Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson s disease, probably as a result of dopamine depletion in the corpus striatum. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears. 

Reserpine depletes cerebral dopamine by preventing intraneuronal storage (see Chapter 6) it is introduced in low doses (eg, 0.25 mg daily), and the daily dose is then built up gradually (eg, by 0.25 mg every week) until benefit occurs or adverse effects become troublesome. A daily dose of 2-5 mg is often effective in suppressing abnormal movements, but adverse effects may include hypotension, depression, sedation, diarrhea, and nasal congestion. Tetrabenazine (12.5-50 mg orally three times daily) resembles reserpine in depleting cerebral dopamine and has less troublesome adverse effects it is now available in the USA. Treatment with postsynaptic dopamine receptor blockers such as phenothiazines and... 

So far we have treated activation and modulation as separate processes. We will want to preserve that distinction even now as we explore their close interaction. In mania, whether it be driven by stimulants or by high levels of endogenous aminergic neuromodulator, the activation level is raised and the tendency to sleep is lowered. In depression, whether it comes in response to amine depletion by drugs like reserpine or to low levels of endogenous neuromodulators, the activation level is always low and the tendency to sleep may be high. There are notable exceptions to these rules, especially in depression, which is sometimes associated with extreme motor agitation and severe insomnia. 

Depression. Depression is our most common mental problem. One in four women and one in ten men will have a major depression during their lifetime.1095 More than 15 million people in the United States are affected by severe depression in any given year and more than 30,000 may commit suicide.1096 1097 Worldwide psychiatric problems, mostly depression, account for 28% of all disabilities.1098 The biogenic amine hypothesis states that depression results from the depletion of neurotransmitters in the areas of the brain involved in sleep, arousal, appetite, sex drive, and psychomotor activity. An excess of transmitters is proposed to give rise to the manic phase of the bipolar (manic-depressive) cycle that is sometimes observed. In support of this hypothesis is the observation that administration of reserpine precipitates depression, which may be serious in 15-20% of hypertensive patients receiving the drug. Similar effects are observed with the dopa decarboxylase inhibitor a-methyldopa... 

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