Molindone

Molindone is used in the treatment of schizophrenia. Available forms Molindone is available in the form of 5, 10, 25, and 50mg oral tablets. ==Adverse effects==

The side effect profile of molindone is similar to that of other typical antipsychotics. This includes extrapyramidal symptoms and tardive dyskinesia. Molindone may have less potential for sedation than certain other antipsychotics owing to its lack of antihistamine activity. It has little or no anticholinergic activity and may be less likely than certain other antipsychotics to cause orthostatic hypotension. ==Pharmacology==

Pharmacodynamics Molindone is known to act as a potent antagonist of the dopamine D2 receptor ( = 84–140nM) and of the serotonin 5-HT2B receptor ( = 410nM). It is far less potent as an antagonist of the dopamine D1, D3, and D5 receptors ( = 3,200–8,300nM) and of the serotonin 5-HT2A receptor ( = 14,000nM). Molindone is described as an antipsychotic, sedative, and major tranquilizer. In animals, it reduces spontaneous locomotor activity, inhibits conditioned avoidance responses, produces catalepsy and hypothermia, and limits aggression in monkeys. However, very high concentrations (~100,000nM) and high doses (10 and 40mg/kg) are required for monoamine oxidase inhibition. Pharmacokinetics The elimination half-life of molindone is approximately 2hours. This half-life is much shorter than that of most other antipsychotics. Concentrations of molindone are negligible 12hours following the last dose even it is used at high doses. Lithium has been found to prolong the half-life of molindone by at least 4-fold. In spite of the preceding findings, the duration of action of molindone is 24 to 36hours. It has been suggested that the antipsychotic effects of molindone may be mediated by active metabolites rather than by molindone itself. ==Chemistry==

Molindone is an indole derivative or dihydroindole and is structurally distinct from many other antipsychotics. Newer patent: Condensation of oximinoketone 2 (from nitrosation of 3-pentanone), with cyclohexane-1,3-dione (1) in the presence of zinc and acetic acid leads directly to the partly reduced indole derivative 6. The transformation may be rationalized by assuming as the first step, reduction of 2 to the corresponding α-aminoketone. Conjugate addition of the amine to 1 followed by elimination of hydroxide (as water) would give ene-aminoketone 3. This enamine may be assumed to be in tautomeric equilibrium with imine 4. Aldol condensation of the side chain carbonyl group with the doubly activated ring methylene group would then result in cyclization to pyrrole 5; simple tautomeric transformation would then give the observed product. Mannich reaction of 6 with formaldehyde and morpholine gives the tranquilizer molindone (7). ==History==

Molindone was first described in the literature by 1966. It was first approved for medical use, to treat schizophrenia, in 1974 in the United States. ==Society and culture==

Availability Molindone has been marketed in the United States, Finland, and Hong Kong. In 2000, it was available only in these three countries. The drug was discontinued by its original supplier, Endo Pharmaceuticals, on January 13, 2010. After having been produced and subsequently discontinued by Core Pharma in 2015 to 2017, molindone is available again from Epic Pharma effective December 2018. ==Research==

Depression and anxiety Molindone has been studied in the treatment of depression and anxiety. Many other antipsychotics have also shown clinical anti-aggressive effects. This study eventually led to molindone being developed for treatment of impulsive aggression in youth much later on. As of May 2024, it is in phase 3 clinical trials for this indication. Negative effectiveness findings in a phase 3 trial have been reported. The exact mechanism of action of molindone for this indication is unknown, but has been proposed to be related to dopamine D2 and serotonin 5-HT2B receptor antagonism. ==References==