Ongoing phase 2/3 trials of psychotropic drugs: is help finally on the way?

In their comprehensive review, Correll et al ¹ identify four important problem areas that have slowed the development of better pharmacological treatments for people suffering from serious mental disorders, such as schizophrenia, major depressive disorder and bipolar disorder. These impediments include the limited knowledge of the pathophysiology of these disorders; the lack of biological markers to stratify patient groups and individualize treatment se­lection; a restricted number of poten­tial­ly relevant mechanisms of action for nov­el drug development; and a variety of method­ological problems that impair signal de­tec­tion in randomized controlled trials (RCTs).

The review is divided into two segments, one summarizing current research on prom­ising drugs being studied in phase 2 or 3 trials, and the other reviewing methodological refinements that might improve the validity and efficiency of clinical research. In this piece, I will largely focus on the areas that I know best, though the authors’ review of recent developments in the treatment of dementia provides a sobering summary of just how much more work there needs to be done.

For acute treatment of schizophrenia and related disorders, the authors identified 176 trials of a diverse group of compounds, large­ly targeting non‐dopaminergic mech­anisms. They found that only about one quarter of these RCTs had reported results and, a­mong these, only about one quarter dem­on­strat­ed efficacy on the primary dependent measure. Further, they determined that only a handful of these drugs had progressed to phase 3.

Two of the most interesting drugs that have moved on to phase 3 are KarXT, which is a fixed combination of xanomeline – a mus­carinic M1/M4 agonist – and the pe­riph­er­ally acting anticholinergic trospium chlo­ride ² , and ulotaront, the first trace amine‐associated receptor 1 (TAAR‐1) agonist to show efficacy in a placebo controlled trial ³ . Despite their substantial differences, both drugs are particularly noteworthy because of the absence of extrapyramidal and metabolic side effects. If efficacy and safety are confirmed in the next phase of larger scale studies, these compounds could go a long way towards addressing critical un­met needs, by virtue of having novel mecha­nisms of action and more favorable toler­ability profiles. Unfortunately, the review also doc­uments that another important un­met need in this area of therapeutics, namely treatment of negative symptoms, has not yield­ed much in the way of truly novel and prom­ising developments.

It was not too long ago that the process of discovery of truly novel drugs for treatment of major depressive disorder seemed like an exercise in futility, as one after another drug with theoretically relevant mechanisms of ac­tion failed to delivery significant clinical ef­fects ⁴ . What a difference a decade can make! The authors identified nearly 180 trials and found that 19 out of 43 RCTs had reported significant effects.

The serendipitous observation that intravenous ketamine – at sub‐anesthetic doses – could have rapid and large antidepressant effects stimulated a wave of drug development focused on glutamatergic neurotransmission. The paradigm‐changing nature of in­‐travenous ketamine therapy extended beyond its mode of delivery and the rapidity of effects: this is a controlled substance, yet its antidepressant effects, which typically persist for 3‐5 days, extend long after the intoxicating effects have dissipated.

It was also noteworthy that the dissociative and euphorogenic effects of intravenous ketamine were not closely linked to the likeli­hood of symptom improvement, which fur­ther suggested that the properties that lead to drug misuse or abuse are not essential to its antidepressant effects ⁴ . Nevertheless, there was considerable caution about the po­tential risks of this treatment, and nearly 20 years elapsed between the first observa­tions of antidepressant effects and the ap­proval by the US Food and Drug Administration (FDA) of the first treatment directly resulting from this line of research.

Beyond harvesting the “low hanging fruit”, i.e. other modes of administration of ketamine and commercialization of its stereoisomers (S‐ and R‐ketamine), research has also focused on other molecules that modulate glutamatergic neurotransmission, including a proprietary combination of dextromethorphan – the ancient cough suppressant – and bupropion ⁵ . This medication has recently been approved by the FDA for treatment of major depressive disorder, becoming the first orally administered treatment in this line of therapeutics. A second orally administered medication, esmethadone ⁶ , is now in phase 3. Interestingly, despite its lineage, this last drug is essentially devoid of opioid activity.

Another line of research explored the ther­apeutic implications of the observation that GABAergic neurons modulate gluta­matergic neurotransmission. Demonstration that a short course of intravenous treat­ment with the neurosteroid brexanolone, an allosteric modulator of GABA‐A, could produce rapid antidepressant effects in wo­men with postpartum depression quick­ly led to identification of a closely related compound, zuranolone, suitable for oral ad­ministration. Importantly, though the ori­gi­nal discovery plan of these compounds was directed at postpartum depression, it was quickly recognized that this mechanism of action was relevant to treatment of depression in both men and women ⁷ . Of additional interest is the possibility that these treatments are suitable for intermittent or periodic treatment.

Interestingly, whereas the antidepres­sant effects of the treatments reviewed above appear to be unrelated to their potentially intoxicating or psychotomimetic effects, the fact that ketamine is a controlled substance may have helped open the door to reexamination of the therapeutic poten­tial of hallucinogens such as psilocybin ⁸ . In this case, the intensity of the “psychedelic” experience is thought to be essential to the antidepressant effect, as is the belief – on clinical/experiential grounds – that the “trip” should be carefully guided to ­maximize the ­clinical benefit. As few safety concerns have emerged to date from phase 2 and early phase 3 studies of psilocybin, it may be that the field will need to wait until post‐marketing for more rigorous studies to examine the amount and content of the adjunctive psychotherapeutic support necessary for an optimal result.

In contrast to developments in schizophrenia and major depressive disorder, the authors were unable to identify any drugs currently in development for either acute treatment of mania or prophylaxis of bipolar disorder. Of course, it is almost axiomatic that, once a compound has established efficacy for treatment of acute schizophrenia, interest in its use in mania will follow. Moreover, they identified no compounds in phase 3 for treatment of bipolar depression. That said, the regulatory pathway of lurasidone and, more recently, lumetaperone illustrates that drugs such as KarXT and ulotaront may hold promise for people with bipolar depression, as might drugs such as zuranolone and esmethadone.

The second segment of Correll et al's pa­per provides an excellent summary of some of the most recent strategies used to improve signal detection in clinical trials. As diagnostic heterogeneity, imprecision of measurement, and various factors that inflate the impact of placebo‐expectancy effects on RCT outcomes, will continue to be a way of life for researchers for the foreseeable future, it is wise to incorporate as many of the authors’ recommendations as practicable in the next generation of research.

I believe that our best hope for improved signal detection is the establishment of net­works of rigorously trained and monitored investigators working together with access to populations of “real‐world patients”, in a manner analogous to the way that our peers working in cancer treatment have collaborated for the past few decades.