Reserpine

Reserpine is recommended as an alternative drug for treating hypertension by the JNC 8. A 2016 Cochrane review found reserpine to be as effective as other first-line antihypertensive drugs for lowering of blood pressure. The reserpine–thiazide diuretic combination is one of the few drug treatments shown to reduce mortality in randomized controlled trials: The Hypertension Detection and Follow-up Program, the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents, and the Systolic Hypertension in the Elderly Program. Moreover, reserpine was included as a secondary antihypertensive option for patients who did not achieve blood pressure lowering targets in the ALLHAT study. It was previously used to treat symptoms of dyskinesia in patients with Huntington's disease, but alternative medications are preferred today. The daily dose of reserpine in antihypertensive treatment is as low as 0.05 to 0.25 mg. The use of reserpine as an antipsychotic drug had been nearly completely abandoned, but more recently it made a comeback as adjunctive treatment, in combination with other antipsychotics, so that more refractory patients get dopamine blockade from the other antipsychotic, and dopamine depletion from reserpine. Doses for this kind of adjunctive goal can be kept low, resulting in better tolerability. Originally, doses of 0.5 mg to 40 mg daily were used to treat psychotic diseases. Doses in excess of 3 mg daily often required use of an anticholinergic drug to combat excessive cholinergic activity in many parts of the body as well as parkinsonism. For adjunctive treatment, doses are typically kept at or below 0.25 mg twice a day. ==Adverse effects==

At doses of less than 0.2 mg/day, reserpine has few adverse effects, the most common of which is nasal congestion. Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea. The drug causes hypotension and bradycardia and may worsen asthma. Congested nose and erectile dysfunction are other consequences of alpha-blockade. Central nervous system effects at higher doses (0.5 mg or higher) include drowsiness, dizziness, nightmares, Parkinsonism, general weakness and fatigue. High dose studies in rodents found reserpine to cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. It may also cause hyperprolactinemia. It may produce an excessive decline in blood pressure at doses needed for treatment of anxiety, depression, or psychosis. ==Mechanism of action==

Reserpine irreversibly blocks the H+-coupled vesicular monoamine transporters, VMAT1 and VMAT2. VMAT1 is mostly expressed in neuroendocrine cells. VMAT2 is mostly expressed in neurons. Thus, it is the blockade of neuronal VMAT2 by reserpine that inhibits uptake and reduces stores of the monoamine neurotransmitters norepinephrine, dopamine, serotonin and histamine in the synaptic vesicles of neurons. VMAT2 normally transports free intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal into presynaptic vesicles for subsequent release into the synaptic cleft ("exocytosis"). Unprotected neurotransmitters are metabolized by MAO (as well as by COMT), attached to the outer membrane of the mitochondria in the cytosol of the axon terminals, and consequently never excite the post-synaptic cell. Thus, reserpine increases removal of monoamine neurotransmitters from neurons, decreasing the size of the neurotransmitter pools, and thereby decreasing the amplitude of neurotransmitter release. As it may take the body days to weeks to replenish the depleted VMATs, reserpine's effects are long-lasting. ==Biosynthetic pathway==

Reserpine is one of dozens of indole alkaloids isolated from the plant Rauvolfia serpentina. In the Rauvolfia plant, tryptophan is the starting material in the biosynthetic pathway of reserpine, and is converted to tryptamine by tryptophan decarboxylase enzyme. Tryptamine is combined with secologanin in the presence of strictosidine synthetase enzyme and yields strictosidine. Various enzymatic conversion reactions lead to the synthesis of reserpine from strictosidine. ==History==

Reserpine was isolated in 1952 from the dried root of Rauvolfia serpentina (Indian snakeroot), which had been known as Sarpagandha and had been used for centuries in India for the treatment of insanity, as well as fever and snakebites — Mahatma Gandhi used it as a tranquilizer. It was first used in the United States by Robert Wallace Wilkins in 1950. Its molecular structure was elucidated in 1953 and natural configuration published in 1955. It was introduced in 1954, two years after chlorpromazine. The first total synthesis was accomplished by R. B. Woodward in 1958. Reserpine-induced depletion of monoamine neurotransmitters in the synapse allegedly caused depression and was cited as evidence that a "chemical imbalance", namely low levels of monoamine neurotransmitters, is what causes clinical depression in humans. A 2003 review showed barely any evidence that reserpine actually causes depression in either human patients or animal models. Notably, reserpine was the first compound ever to be shown to be an effective antidepressant in a randomized placebo-controlled trial. A 2022 systematic review found that studies of the influence of reserpine on mood were highly inconsistent, with similar proportions of studies reporting depressogenic effects, no influence on mood, and antidepressant effects. The quality of evidence was limited, and only a subset of studies were randomized controlled trials. Although reserpine itself cannot provide good evidence for the monoamine hypothesis of depression, other lines of evidence support the idea that boosting serotonin or norepinephrine can effectively treat depression, as shown by SSRIs, SNRIs, and tricyclic antidepressants. ==Veterinary use==

Reserpine is used as a long-acting tranquilizer to subdue excitable or difficult horses and has been used illicitly for the sedation of show horses, for-sale horses, and in other circumstances where a "quieter" horse might be desired. It is also used in dart guns. ==Research==

Animal model of depression and amotivation Similarly to tetrabenazine, reserpine, via depletion of monoamine neurotransmitters, produces depression-like effects and lack of motivation or fatigue-like symptoms in animals. This can be useful in evaluating new antidepressants and psychostimulant-like agents. ==References==