Another important feature of Psychopharmacology 3.0 is the repurposing of hallucinogens into novel therapies for posttraumatic stress disorder, anxiety, and depression.1 The opioid system is being recognized as another key player in depression, with many studies showing buprenorphine has antidepressant and anti-suicidal properties2 and the recent finding that pre-treatment with naloxone blocks the rapid antidepressive effects of ketamine.3 This finding casts doubt on the notion that the antidepressant mechanism of action of ketamine is solely mediated via its antagonism of the glutamate N-methyl-D-aspartate (NMDA) receptor. Another imminent innovative antidepressant mechanism of action is represented by brexanolone, an allosteric modulator of GABA-A receptors (which are known to become dormant during pregnancy and are not reactivated after delivery in women who develop postpartum depression).
These early developments in Psychopharmacology 3.0 augur well for the future. Companies in the pharmaceutical industry (which are hated by many, and even demonized and kept at arm’s length by major medical schools) are, in fact, the only entities in the world that develop new medications for psychiatric disorders, 82% of which still have no FDA-approved drug.4 Psychiatric researchers and clinicians should collaborate and advise the pharmaceutical companies about the urgent or unmet needs of psychiatric patients so they can target those unmet needs with their massive R&D resources.
In that spirit, here is my wish list of therapeutic targets that I hope will emerge during the Psychopharmacology 3.0 era and beyond:
1. New mechanisms of action for antipsychotics, based on emerging neurobiological research in schizophrenia and related psychoses, such as:
- Inhibit microglia activation
- Repair mitochondrial dysfunction
- Modulate the hypofunctional NMDA receptors
- Inhibit apoptosis
- Enhance neurogenesis
- Repair myelin pathology
- Inhibit neuroinflammation and oxidative stress
- Increase neurotropic growth factors
- Neurosteroid therapies (including estrogen)
- Exploit the microbiome influence on both the enteric and cephalic brains
2. Long-acting injectable antidepressants and mood stabilizers, because there is a malignant transformation into treatment-resistance in mood disorders after recurrent episodes due to nonadherence.5
3. Treatments for personality disorders, especially borderline and antisocial personality disorders.
4. An effective treatment for alcoholism.
5. Pharmacotherapy for aggression.
6. Vaccines for substance use.
7. Stage-specific pharmacotherapies (because the neurobiology of prodromal, first-episode, and multiple-episode patients have been shown to be quite different).
8. Drugs for epigenetic modulation to inhibit risk genes and to over-express protective genes.
It may take decades and hundreds of billions (even trillions) of R&D investment to accomplish the above, but I remain excited about the prospects of astounding psychopharmacologic advances to treat the disorders of the mind. Precision psychiatry advances will also expedite the selection of the right medication for each patient by employing predictive biomarkers. Breakthrough methodologies, such as pluripotent stem cells, opto-genetics, and clustered regularly interspaced short palindromic repeats (CRISPR), promise to revolutionize the biology, diagnosis, treatment, and prevention of various neuropsychiatric disorders.
The future of psychopharmacology is bright, if adequate resources are invested. The current direct and indirect costs of mental disorders and addictions are in the hundreds of billions of dollars annually. Only intensive research and disruptive discoveries will have the salutary dual effect of healing disease and reducing the economic burden of neuropsychiatric disorders. Psychopharmacology 3.0 advances, along with nonpharmacologic therapies such as neuromodulation (electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, and a dozen other techniques in development). Together with the indispensable evidence-based psychotherapies such as cognitive-behavioral therapy, dialectical behavior therapy, and interpersonal psychotherapy, psychopharmacology represents the leading edge of progress in psychiatric treatment. The psychiatrists of 1952 could only fantasize about what has since become a reality in healing ailing minds.
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