Novel Treatments for Schizophrenia Reduce Symptoms and Adverse Effects

Promising medications for schizophrenia are aimed at the difficult targets of negative symptoms and tardive dyskinesia, and innovative nonpharmacologic approaches are emerging as potent treatments for restoring cognitive and social functioning.

The negative symptoms of schizophrenia, marked by withdrawal and reduced capacity for social interaction, have been less responsive to treatment than the “positive,” florid symptoms of psychosis such as hallucinations. Part of the challenge in addressing negative symptoms of schizophrenia has been in distinguishing them from antipsychotic drug adverse effects and from concurrent mood disorders.

An investigational compound, designated MIN-101 by Minerva Neurosciences, is in early clinical trials in patients with prominent negative symptoms but sufficiently stable schizophrenia illness to have their antipsychotic medication discontinued during the testing. The compound acts on the sigma-2 and 5-HT2a serotonin receptors, without direct action on dopamine, histamine, cholinergic, or muscarinic sites.

The results of a report of a 12-week phase 2b trial, published online on July 28 in the American Journal of Psychiatry, suggest that the investigational agent is effective in reducing negative symptoms, while the trial design and analysis effectively removed antipsychotic drug adverse effects and mood symptoms as confounders.¹

Michael Davidson, MD, chief medical officer at Minerva Neurosciences, and colleagues cautioned that early clinical trial results do not necessarily translate to clinical practice, but they are nevertheless optimistic.

“There was a noticeable and statistically significantly greater change in CGI [clinical global impression] severity and improvement scores in the MIN-101 64 mg/day group compared with the placebo group,” the investigators wrote. “Furthermore, the effect sizes for negative symptoms reported here are higher than those of currently marketed drugs indicated for schizophrenia and of many drugs utilized to treat chronic disease in general medicine.”

TACKLING TARDIVE DYSKINESIA

Tardive dyskinesia (TD), emerging with neuroleptic effects of antipsychotic actions on dopamine receptors, presents the clinical dilemma of whether to discontinue or reduce dose and worsen schizophrenia symptoms or to continue antipsychotic treatment—possibly with an agent having less liability for causing TD but little capacity for reversing it—and contribute to the likelihood of TD becoming irreversible.

An alternative approach to reducing severity of the movement disorder has become available with the recent FDA approval of deutetrabenazine (Austedo, Auspex Pharmaceuticals). The agent, previously approved for Huntington's chorea, was shown in a large phase III trial to reduce TD symptoms regardless of whether patients continue or discontinue their antipsychotic.

Deutetrabenazine was administered for 12 weeks to 298 patients with TD who were randomized to receive 1 of 3 doses or placebo at multiple sites in the United States and Europe.

The primary measure of effectiveness was improvement on the Abnormal Involuntary Movement Scale (AIMS). Deutetrabenazine was associated with a reduction in AIMS score from baseline to week 12 of —3.3 points in the 36 mg/day group, –3.2 points with 24 mg/day, –2.1 points with 12 mg/day, and –1.4 points with placebo.

Karen Anderson, MD, director, Huntington’s Disease Care, Education and Research Center, Georgetown University Hospital, Washington DC, and colleagues reported in the August issue of Lancet Psychiatry that deutetrabenazine in the 24 mg/day and 36 mg/day doses provided a significant reduction in TD, with a favorable safety and tolerability profile.²

“This finding suggests that dosing regimens could be individualized and tailored for patients on the basis of dyskinesia control and tolerability. Furthermore, treatment of tardive dyskinesia with deutetrabenazine might allow uninterrupted use of concomitant dopamine receptor antagonists for underlying psychiatric conditions,” Anderson and colleagues concluded.

PROVING PSYCHOSOCIAL THERAPIES FOR PSYCHOTIC ILLNESS

A recovery-oriented cognitive therapy (CT-R) developed by Paul Grant, PhD, and colleagues in the Department of Psychiatry, University of Pennsylvania, has previously been shown in a randomized controlled trial in low-functioning individuals with schizophrenia to improve global functioning and reduce avolition/apathy as well as positive symptoms over an 18-month treatment period.

CT-R was developed for individuals with schizophrenia who are isolated from interactions with others and have limited motivation to engage in activities. The first component of CT-R employs various methods to engage and establish a connection with the individual, ranging from listening to music to going for a walk. The therapist then identifies personal aspirations, such as obtaining a job or reconnecting to family. The process moves into guidance to attain a series of nested success experiences in the direction of fulfilling those aspirations.

Grant and colleagues undertook a 6-month follow-up of the subjects in the original trial and reported in a June online posting in Psychiatric Services that the improvements over baseline were maintained across the follow-up period when therapy was withdrawn.³ The results support, they indicate, “the notion that CT-R produces an enduring change in beliefs and skills that enable individuals to continue to maintain gains without their therapist.”

A group at the University of Navarra, Pamplona, Spain, recently reported the success of a pilot study to improve social skills in individuals with schizophrenia through outpatient psychotherapy groups based on the recently developed Metacognition-Oriented Social Skills Training (MOSST) intervention.

Felix Inchausti, PhD, and colleagues acknowledge that previous reviews, including a Cochrane Collaboration review, have not found that social skills training has evidenced sufficient effect size to warrant recommending it over standard care. Most programs, however, have neglected the promotion of metacognitive abilities, according to Inchausti and colleagues. “Metacognition” and “social cognition” are umbrella terms for the mental processes that underlie social interaction, they explain.

Despite the importance of social skills, previous evaluations of MOSST have been limited to case studies. Inchausti and colleagues undertook the pilot study with 12 outpatients with schizophrenia to determine the feasibility of conducting a larger, randomized controlled trial of the acceptance and effectiveness of the method. The patients were offered 16 group sessions with MOSST, with psychosocial functioning and metacognition assessed at baseline and end of treatment with the Personal and Social Performance Scale and the Metacognition Assessment Scale—Abbreviated, respectively.

Inchausti and colleagues published their findings in June online in BMC Psychiatry. Despite limitations inherent in a small pilot study, they were encouraged by the results and reported “outpatients with schizophrenia will accept metacognitive therapy for social skills training and evidence improvements in psychosocial functioning and metacognition.”⁴

REFERENCES

1. Davidson M. Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. American Journal of Psychiatry. 2017. http://ajp.psychiatryonline.org/doi/full/10.1176/appi. ajp.2017.17010122. Accessed August 22, 2017.

2. Anderson K, Stamler D, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017. http:// www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(17)30236-5/ fulltext. Accessed August 19, 2017.

3. Grant, P, Bredemeier, K, Beck, A. (2017). Six-Month Follow-Up of Recovery- Oriented Cognitive Therapy for Low-Functioning Individuals With Schizophrenia. Psychiatric Services. http://ps.psychiatryonline.org/doi/full/10.1176/appi. ps.201600413. Accessed August 25, 2017.

4. Inchausti F, García-Poveda N, et al.. (2017). A pilot study on feasibility, acceptance and effectiveness of metacognitive-oriented social skills training in schizophrenia. BMC Psychiatry, 17(1). https://bmcpsychiatry.biomedcentral. com/articles/10.1186/s12888-017-1378-z. Accessed August 20, 2017.