New Antipsychotic Medications in the Last Decade.

PURPOSE OF REVIEW: Over the last ten years, the treatment of psychosis has seen a near explosion of creative development in both novel agents and new delivery modalities. The current review summarizes these developments over the past decade (2011-2020). We performed a systematic review utilizing PubMed and PsychInfo with the aim of identifying all the RCT and related analyses in adults with psychosis (schizophrenia and mania). RECENT FINDINGS: We identified 11 significant developments: the introduction of new antipsychotics cariprazine, brexpiprazole, lumateperone, and pimavanserin; introduction of new delivery methods: subcutaneous long-acting risperidone, aripiprazole lauroxil, transdermal asenapine, and inhaled loxapine; and the introduction of new approaches such as olanzapine/samidorphan for olanzapine-associated weight gain, examination of the TAAR1 agonist SEP 363,856 as a test of concept, and the combination of Xanomeline/Trospium, an M1 and M4 muscarinic receptor agonist in conjunction with a peripheral anticholinergic. Last decade has seen a tremendous development in second-generation antipsychotics which provides unprecedented treatment options for clinicians in treating psychosis.

Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia.

Schizophrenia is a severe mental illness that has its onset in late adolescence or early adulthood and is associated with significant dysfunction across multiple domains. The pathogenesis of schizophrenia remains unknown, but physiologic understanding of the illness has been driven by the dopamine hypothesis. However, acetylcholine (ACh) clearly plays a role with mixed results regarding effect on psychosis. Selective muscarinic M1 and M4 agonists, such as xanomeline, originally developed to aid in cognitive loss with Alzheimer's, showed promise in proof-of-concept study in 20 patients with schizophrenia. Unfortunately, tolerability problems made muscarinic agonists impractical in either condition. However, coadministration of trospium, a lipophobic, non-selective muscarinic antagonist previously used for the treatment of overactive bladder, with xanomeline resulted in a significant reduction of cholinergic adverse effects. A recent randomized, placebo-controlled study of the antipsychotic effects of this combination in 182 patients with acute psychosis revealed improved tolerability with 80% of subjects staying to the end of the 5 weeks study. At the end of the trial, the treatment group saw a -17.4 change in the positive and negative symptom scale (PANSS) score from baseline compared to a -5.9 change in the placebo arm (P < 0.001). Furthermore, the negative symptom subscore, was also superior in the active arm (P < 0.001). These early studies are exciting because they suggest that the cholinergic system may be recruited to treat a severe and disabling disorder with suboptimal treatment options. Xanomeline-trospium combination is currently in phase III studies.

Catatonia Secondary to Depolarization Block.

Catatonia is a severe psychomotor disorder that is associated with a 60-fold increased risk of premature death. Its occurrence has been associated with multiple psychiatric diagnoses, the most common being type I bipolar disorder. Catatonia can be understood as a disorder of ion dysregulation with reduced clearance of intracellular sodium ions. As the intraneuronal sodium concentration increases, the transmembrane potential is increased, and the resting potential may ultimately depolarize above the cellular threshold potential creating a condition known as depolarization block. Neurons in depolarization block do not respond to stimulation but are constantly releasing neurotransmitter; they mirror the clinical state of catatonia - active but non-responsive. Hyperpolarizing neurons, e.g., with benzodiazepines, is the most effective treatment.

Evaluating lumateperone for its use in treating depressive episodes associated with bipolar I or II disorder in adults.

INTRODUCTION: Lumateperone is a novel antipsychotic medication that has recently received approval by the United States Food and Drug Administration for treatment of major depressive episodes of type I and II bipolar disorder. It is approved for use as monotherapy or as an adjunctive treatment to lithium or valproic acid. AREAS COVERED: Clinical trials performed with lumateperone for bipolar disorder were reviewed. Additionally, pharmacodynamic actions of lumateperone are reviewed. Lumateperone is superior to placebo whether used alone or in combination with a mood stabilizer in patients with type I or type II bipolar disorder. It achieves this effect with minimal dopamine blockade-related side effects due to less than 50% dopamine D2 receptor occupancy. While the pharmacodynamic profile of lumateperone is unique, the mechanism of action in bipolar depression remains obscure. EXPERT OPINION: Lumateperone is an antipsychotic with full antagonist effects at the post-synaptic D2, and partial agonist effects at the presynaptic D2. This unique profile allows for both antipsychotic and antidepressant effects at the same dose, which does not produce dopamine-related side effects. Consequently, lumateperone is exceptionally well tolerated compared to other antidepressant-acting antipsychotic agents. It is now the only agent approved as an adjunct to the mood stabilizer for bipolar II depression.

Pharmacologic treatment and management of bipolar disorder in adolescents.

INTRODUCTION: The importance of the appropriate therapeutic interventions in children and adolescents with bipolar disorder (BD) cannot be overstated since treatment choices and their consequences may have effects into adulthood. AREAS COVERED: Randomized clinical trials (RCTs) investigating treatment of mania, bipolar depression, and maintenance in adolescents with BD are reviewed. When RCTs are not available or are inadequate, naturalistic data or open studies are also reviewed. EXPERT OPINION: Efficacy and safety of pharmaceutical agents in adolescents with BD appear to mirror adults with BD. Lithium/mood stabilizers are preferred first-line agents over antipsychotic medications, but the latter are second-line agents particularly in bipolar depression. When lithium is used, serum levels approaching 1.0 mEq/L are reasonable since younger people appear to require/tolerate higher levels. Among the antipsychotics, quetiapine appeared to be minimally better than risperidone while risperidone was associated with greater adverse events. Antipsychotics with antidepressant activity in adults also appear to have antidepressant effects in youths. Use of antidepressants in bipolar depression is generally not recommended although it may be reasonable in specific clinical situations. The similarities between adolescent and adult outcomes suggest that it is reasonable to utilize adult data to aid with clinical decision making in adolescents with BD.

Treatment-Resistant Bipolar Depression: Therapeutic Trends, Challenges and Future Directions.

Introduction: Bipolar disorder (BD) is a chronic mental illness impacting 1-2% of the population worldwide and causing high rates of functional impairment. Patients with BD spend most of their time in depressive episodes and up to one-third of patients do not respond to adequate doses of medications. Although no consensus exists for definition of treatment-resistant bipolar depression (TRBD), failure of symptoms improvement despite an adequate trial of two therapeutic agents is a common theme of TRBD. In this paper, we review the evidence base of therapeutic interventions, challenges, and potential future directions for TRBD. Methods: We conducted a literature search for randomized controlled trials on PubMed for the treatment of TRBD and ongoing trials for the treatment of TRBD/bipolar depression on clinicaltrials.gov. Results: Several therapeutic agents have been investigated for TRBD. Adjunctive pramipexole and modafinil have data supporting short-term efficacy in TRBD, along with limited data for racemic intravenous ketamine. Celecoxib augmentation of escitalopram and treatment with metformin in patients with insulin resistance showed promising results. Right unilateral electroconvulsive therapy displayed statistically significant response rate and improvement, but not remission compared to pharmacotherapy. Trials for transcranial magnetic stimulation (TMS) have failed to show a significant difference from sham treatment in TRBD. Future Trends: Pharmacological treatments with novel mechanisms of actions like brexpiprazole and vortioxetine are being investigated following successes in unipolar depression. Modified TMS protocols such as accelerated TMS are under investigation. Innovative approaches like psychedelic-assisted psychotherapy, interleukin-2, fecal microbiota transplantation and multipotent stromal cells are being studied. Conclusion: Evidence on current treatment modalities for TRBD is limited with low efficacy. More research is needed for successful treatment of TRBD. Effective therapies and innovative approaches to treatment are being investigated and could show promise.

Chlordiazepoxide-induced delirium in a patient undergoing alcohol withdrawal: a case report.

BACKGROUND: Ethanol dependence is associated with a discontinuation withdrawal delirium. Chlordiazepoxide is frequently successfully used in its treatment. CASE PRESENTATION: A 27-year-old, Caucasian female with ethanol dependence who had objective symptoms of withdrawal experienced worsening of her delirium after administration of chlordiazepoxide, but improved with lorazepam and cleared with discontinuation of benzodiazepine administration. CONCLUSIONS: Worsening of delirium appears to be related to the specific use of chlordiazepoxide, but the mechanism of this effect is not clear. While this case does not alter the standard care of ethanol dependence, it does alert clinicians that our treatment approach may not be fully benign.