Clinically Relevant Developments in Psychiatry

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RESEARCH UPDATE

Dr Aftab is a Geriatric Psychiatry Fellow at University of California San Diego in La Jolla, CA. He is also a member of the Psychiatric Times Advisory Board.

Psychiatry continues to evolve rapidly, advancing our understanding of the complex etiology of mental disorders with each year and bringing advances in psychiatric treatments; 2018 was no exception. Here is a selection of eight research developments that may impact psychiatric clinical practice in the coming years. This list is neither comprehensive nor definitive, but a brief assortment expected to be of interest to a clinical audience. These preliminary findings add to the armamentarium of treatments for a range of psychiatric disorders.

Polygenic risk score for schizophrenia and response to lithium in bipolar disorder

Amare AT, Schubert KO, Hou L, et al. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: a genome-wide association study.JAMA Psychiatry. 2018;75:65-74.

Individual genetic variants associated with schizophrenia have very small effect sizes; however, collectively, these variants determine the genetic susceptibility to schizophrenia. Schizophrenia polygenic risk score is the quantified sum of schizophrenia-associated alleles across many different genetic loci. The genetic overlap between bipolar disorder and schizophrenia has been well-documented.

It is also known that response to lithium in bipolar disorder can be variable. Amare and colleagues investigated whether polygenic risk score for schizophrenia (determined from a genome-wide association study) would be associated with treatment responses to lithium in bipolar disorder. Almost 2600 patients with bipolar disorder who had been treated with lithium were genotyped and assessed for lithium response.

The polygenic score for schizophrenia was inversely associated with lithium treatment response, with low schizophrenia polygenic load being associated with odds ratio of response up to 3.5 compared with high polygenic risk score. Interestingly, genetic variants related to human leukocyte antigen (HLA) complex and inflammatory cytokines appear to be involved in mediating this relationship. This suggests that in patient with bipolar disorder, determination of genetic loading for schizophrenia risk variants could potentially help individualize lithium treatment.

Pre-reactivation propranolol therapy for PTSD

Brunet A, Saumier D, Liu A, Streiner DL, Tremblay J, Pitman RK. Reduction of PTSD symptoms with pre-reactivation propranolol therapy: a randomized controlled trial.Am J Psychiatry. 2018;175:427-433.

Reactivation of a consolidated memory appears to change it from a stable to labile state, where it could potentially be influenced by pharmacologic agents. This hypothesis was investigated for traumatic memories in a double-blinded, randomized placebo-controlled trial by Brunet and colleagues who looked at the impact of pre-reactivation propranolol therapy on PTSD symptoms in weekly treatments over 6 weeks.

Adults (N = 61) with PTSD were randomly assigned to treatment or placebo. Participants were asked by therapists to write a narrative of their trauma with associated bodily sensations in the present tense 90 minutes after propranolol or placebo. Compared with placebo, pre-reactivation propranolol therapy led to statistically significant improvements in the Clinician-Administered PTSD Scale as well as patient-rated PTSD Checklist with a large effect size on these clinical measures.

Cannabidiol as a potential treatment for schizophrenia

McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial.Am J Psychiatry. 2018;175:225-231.

Cannabidiol (CBD), the second most active ingredient in marijuana, has been hypothesized to have antipsychotic effects-in contrast to tetrahydrocannabinol (THC), which may promote or worsen psychosis. McGuire and colleagues undertook an 8-week, multicenter, double-blind, parallel-group study to explore the efficacy and safety of 1000-mg CBD daily as adjunctive treatment to oral antipsychotic medication in 88 patients with schizophrenia.

CBD significantly reduced psychotic symptoms (PANSS difference –1.4 score, 95% CI = –2.5 to –0.2), and more patients on CBD were rated as being improved by their clinicians on the Clinical Global Impressions scale compared with the placebo group. There was also a trending improvement in cognition. Moreover, CBD was well-tolerated without significant adverse effects. Pending replication in larger phase-3 trials, CBD could very well emerge as a novel treatment for psychosis in the future.

Long-term SSRI treatment may delay progression from mild cognitive impairment to dementia

Bartels C, Wagner M, Wolfsgruber S, et al. Impact of SSRI therapy on risk of conversion from mild cognitive impairment to Alzheimer dementia in individuals with previous depression.Am J Psychiatry. 2018;175:232.

An analysis of data from the Alzheimer Disease Neuroimaging Initiative-a multicenter, prospective, longitudinal cohort study of subjects with Alzheimer disease-examined the impact of SSRI treatment in patients with mild cognitive impairment (MCI). Participants (N=755) in the study did not have active symptoms of depression (per study criteria), but researchers looked at prior history of depression and history of antidepressant treatment. They discovered that long-term treatment with SSRIs (treatment duration longer than 4 years) in MCI patients with histories of depression was significantly associated with delayed progression to Alzheimer dementia by 3 years. This effect was not seen with short-term SSRI treatment, treatment with antidepressants other than SSRIs, or no antidepressant treatment. It is not known why this effect was only observed with SSRIs and not with other antidepressants.

Antipsychotic plasma levels in treatment-resistant schizophrenia »

Antipsychotic plasma levels in treatment-resistant schizophrenia

McCutcheon R, Beck K, D’Ambrosio E, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia.Acta Psychiatrica Scand. 2018;137:39-46.

Inadequate response to antipsychotics is commonly seen in clinical practice in patients with schizophrenia, and it is often undetermined to what degree this is a result of medication ineffectiveness or medication underexposure due to non-adherence or rapid metabolism. The answer to this question was explored in a British study by examining antipsychotic plasma levels in 99 patients who had received a provisional diagnosis of treatment-resistant schizophrenia.

Patients were receiving: olanzapine, aripiprazole, amisulpride, risperidone, quetiapine, sulpiride and haloperidol. Just over one-third (35%) of the total sample had subtherapeutic antipsychotics plasma levels, including 12% of patients who had undetectable levels. Rates of hospitalization were higher in individuals with a subtherapeutic plasma level (31% vs 11%).

Black ethnicity and lower dose were significantly associated with subtherapeutic/undetectable plasma levels. Therefore, a substantial percentage of patients clinically identified as treatment-resistant may not truly be treatment-resistant given the lack of therapeutic plasma levels of antipsychotic agents. This highlights the utility of plasma antipsychotic levels in the assessment of treatment-resistant schizophrenia, because patients with subthreshold levels could be managed with long-acting injectables (if adherence is an issue) or with appropriate dose modifications (if there is rapid metabolism of antipsychotic medication).

Transcranial magnetic stimulation approved by FDA for OCD

FDA News Release. FDA permits marketing of transcranial magnetic stimulation for treatment of obsessive compulsive disorder. August 17, 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm617244.htm. Accessed December 11, 2018.

In August 2018 the FDA permitted marketing of the Brainsway Deep Transcranial Magnetic Stimulation (TMS) System for treatment of obsessive compulsive disorder (OCD). This approval was based on results of a randomized, multicenter study of 100 patients with OCD (49 active treatment, 51 sham treatment), 25-min sessions, 5 times a week, for 6 weeks. Over one-third (38%) of patients experienced a response to the TMS device (response was defined as greater than 30% reduction in Yale-Brown Obsessive Compulsive Scale score), compared with 11% of patients in the control group. No serious adverse effects were reported.

The Brainsway TMS device uses a special magnetic coil with a broader target reach than other TMS devices. The treatment protocol was also unique because it involved a brief psychotherapy session before each treatment where a therapist encouraged patients to think about their anxieties and compulsions. TMS has been successfully utilized in clinical practice for the treatment of depression since 2008; now this treatment modality can be extended to the treatment of OCD.

Intranasal esketamine for treatment-resistant depression

Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression. September 4, 2018. https://www.janssen.com/janssen-submits-esketamine-nasal-spray-new-drug-application-us-fda-treatment-resistant-depression. Accessed December 11, 2018.

Janssen Pharmaceutical submitted an application to the FDA seeking approval of esketamine nasal spray for treatment-resistant depression in adults. Esketamine is the S(+) enantiomer of ketamine, an NMDA receptor antagonist, which has been successfully used (off-label) via an intravenous route in the treatment of depression and suicidality with rapid response. Esketamine seeks to replicate the rapid response and efficacy of IV ketamine.

Jansen’s application is based on five phase 3 trials: three short-term studies, one withdrawal maintenance of effect study, and one long-term safety study. These studies demonstrate rapid reduction in depression when esketamine is used in conjunction with an oral antidepressant.

Esketamine is likely to be the first NMDA receptor antagonist to acquire FDA approval for treatment-resistant depression. Of note, esketamine is also under investigation for major depressive disorder with imminent risk for suicide, for which it has received an FDA breakthrough therapy designation.

Brexanolone: a rapidly acting novel treatment for post-partum depression

Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.Lancet. 2018;392:1058-1070.

Brexanolone (SAGE-547) is a positive allosteric modulator of GABA-A receptors. It had shown promise in phase 2 trials for the treatment of moderate to severe post-partum depression. In 2018, results of two large placebo-controlled phase 3 trials were published in Lancet.

A total of 246 women with postpartum depression were randomized to brexanolone or placebo. Brexanolone was administered in a single intravenous injection of 60 or 90 μg/kg per hour over 60 hours. In both trials brexanolone led to a significant and clinically robust reduction in depression scores at 60 hours while being clinically safe and well tolerated. Brexanolone is expected to receive FDA approval for post-partum depression in the near future. An infusion lasting nearly three days poses practical challenges in treatment; however the rapid relief offered by the treatment would greatly improve the lives of mothers suffering from postpartum depression as well as their children.

This article was published on 1/16/19 and has since been updated.