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.
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 M 1 and M 4 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.
Lithium is consistently recommended as first line treatment in bipolar illness in published treatment guidelines. Nonetheless, its clinical use in the United States has declined from over 30% to less than 15% of patients in the 20 years from 1997 through 2016. 1 This sits in stark contrast to the more distant historic image of lithium (Figure 1).In the era of the 1890s, Lithium was celebrated and was considered as a treatment for a variety of human ills felt to arise from gout or the 'uric acid diathesis.' This 'diathesis' included almost any symptom that can be experienced, such as constipation, headache, urogenital disorders, cystitis, neuralgia, even malaria, amongst many other complaints. 2,3 Since high (toxic) concentrations of lithium can dissolve uric acid crystals in vitro, clinicians reasoned that lithium may dissolve uric acid crystals in vivo. From the late 1800s into the
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