From the Editor

Psychopharmacology 3.0

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There is little doubt that the psychopharmacology revolution has been transformational for psychiatry and is also credited for sparking the momentous neuroscience advances of the past half century.

The field of psychiatry, dominated by Freudian psychology for decades, radically evolved from psychoanalysis to pharmacotherapy with the discovery that serious mental disorders are treatable with medications, thus dispensing with the couch.

Prior to 1952, the prevailing dogma was that “madness is irreversible.” That’s why millions of patients with various psychiatric disorders were locked up in institutions, which added to the stigma of mental illness. Then came the first antipsychotic drug, chlorpromazine, which “magically” eliminated the delusions and hallucinations of patients who had been hospitalized for years. That serendipitous and historic discovery was as transformational for psychiatry as penicillin was for infections (yet inexplicably, only the discovery of penicillin received a Nobel Prize). Most people today do not know that before chlorpromazine, 50% of all hospital beds in the U.S. were occupied by psychiatric patients. The massive shuttering of state hospitals in the 1970s and ’80s was a direct consequence of the widespread use of chlorpromazine and its cohort of first-generation antipsychotics (FGAs).

That was Psychopharmacology 1.0, spanning the period 1952 to 1987. It included dozens of FGAs belonging to 6 classes: phenothiazines, thioxanthenes, butyrophenones, dibenzazepines, dihydroindolones, and dibenzodiazepines. Psychopharmacology 1.0 also included monoamine oxidase inhibitors and tricyclic antidepressants for depression, and lithium for bipolar mania. Ironically, clozapine, the incognito seed template of the second-generation antipsychotic (SGA) class, was synthesized in 1959 with the early wave of FGAs, and launched in Europe in 1972, only to be withdrawn in 1974 due to agranulocytosis-induced deaths not recognized during the clinical trials.

The late 1980s ushered in Psychopharmacology 2.0, which was also transformative. It began in 1987 with the introduction of fluoxetine, the first selective serotonin receptor inhibitor. Then clozapine was resurrected in 1988 as the first FDA-approved drug for refractory schizophrenia. Being the first SGA (no acute extrapyramidal side effects at all, in contrast to all FGAs), it became the “mechanistic model” for all other SGA agents, which were introduced starting in 1993. All SGAs were designed by pharmaceutical companies’ medicinal chemists to mimic clozapine’s receptor profile: far stronger affinity to serotonin 5HT-2A receptors than to dopamine D2 receptors. Three partial agonists and several heterocyclic antidepressants were also introduced during this 2.0 era, which continued until approximately 2017. Of the 11 SGAs that were initially approved for schizophrenia, 7 also were approved for bipolar mania, and 2 received an FDA indication for bipolar depression, thus addressing a glaring unmet need.

Psychopharmacology 3.0 has already begun. Its seeds started sprouting over the past few years with the landmark studies of intravenous ketamine, which was demonstrated to reverse severe and refractory depression and suicidal urges within hours of injection. The first ketamine product, esketamine, an intranasal formulation, is expected to be approved by the FDA soon. In the same vein, other rapid-acting antidepressants, a welcome paradigm shift, are being developed, including IV scopolamine, IV rapastinel, and inhalable nitrous oxide.

Three novel and important pharmacologic agents have arrived in this 3.0 era:

  • Pimavanserin, a serotonin 5HT-2A inverse agonist, the first and only non-dopamine–blocking antipsychotic approved by the FDA for the delusions and hallucinations of Parkinson’s disease psychosis. It is currently in clinical trials for schizophrenia and Alzheimer’s disease psychosis (for which nothing is yet approved).
  • Valbenazine, the first drug approved for tardive dyskinesia (TD), the treatment of which had been elusive and remained a huge unmet need for 60 years. Its novel mechanism of action is inhibition of vesicular monoamine transporter 2 (VMAT2), which reduces the putative dopamine supersensitivity of TD.
  • Deutetrabenazine, which was also approved for TD a few months after valbenazine, and has the same mechanism of action. It also was approved for Huntington’s chorea.

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