The third generation of therapeutic innovation and the future of psychopharmacology

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...