Depression and Suicide _ ______________________________________________________________________
Statins Two studies compared statins to placebo as add-on therapy to fluoxetine in the treatment of MDD. In one trial, 30 mg/ day lovastatin for six weeks improved antidepressant effects compared to placebo [322]. The other trial found simvastatin 20 mg/day for six weeks significantly decreased depressive symptoms, but remission did not differ from placebo [323]. Statins have relatively few side effects; the most dangerous— rhabdomyolysis—is a very rare event. Statins are primarily used in prevention of cardiovascular events but may have a more favorable benefit/risk balance than other drugs, such as NSAIDs, considering the high cardiovascular comorbidity in persons with depression [324]. Other less common side effects include myopathy, hepatotoxicity, peripheral neu- ropathy, impaired myocardial contractility, and autoimmune dysfunction. Silexan Silexan is a substance derived from Lavandula angustifolia flowers that increases extracellular serotonin levels. Approved in Germany for the treatment of restlessness related to anxious mood, its antidepressant effects were tested in a random- ized controlled trial of 318 patients with mixed anxiety and depressive disorder. Silexan (vs. placebo) significantly reduced MADRS and Hamilton Rating Scale for Anxiety (HAM-A) scores. Antidepressant effects were noted after 2 weeks, became statistically significant at 4 weeks, and remained significant through the 10-week trial [123; 321]. Psilocybin Psilocybin is a classical psychedelic and naturally occurring alkaloid found in the Psilocybe genus of mushrooms [325]. Its potential efficacy in the treatment of depression is a recent focus of research interest. The feasibility, safety, and efficacy of open-label psilocybin were studied in 12 patients with treatment-resistant depression (2 to 13 failed antidepressant trials). All patients received 10-mg (low-dose) oral psilocybin, 25-mg (high-dose) psilocybin one week later, and psychologic support during all sessions. Relative to baseline, depressive symptoms were markedly reduced one week and three months after high-dose treatment. Remission was achieved by 67% at one week and 42% at three months. Marked and sustained improvements in anxiety and anhedonia were also noted. Psilocybin was well tolerated by all patients, without serious or unexpected adverse events [325]. Two psilocybin treatment studies in patients with life- threatening cancer and high levels of depressive and anxious distress were published in 2016. One trial compared low-dose psilocybin (0.3 mg/kg) with niacin placebo, and the other trial compared low-dose (1 or 3 mg/70 kg) and high-dose (22 or 30
effects last up to 10 weeks with repeat dosing. The drug has no psychotomimetic effects, may be neuroprotective, and may enhance aspects of learning and memory. The long-lasting therapeutic benefits are explained by significant effects on metaplasticity processes in the medial prefrontal cortex and hippocampus [316; 317]. Buprenorphine Opioids were widely used as depression treatment from roughly 1850 until 1956, when they were replaced by standard anti- depressants. Their antidepressant potential has rarely been studied in the past 60 years, but this seems to be changing. The synthetic opioid buprenorphine is a partial mu opioid recep- tor agonist and kappa opioid receptor antagonist. It is safer in overdose with substantially less euphoria than traditional opioid analgesics such as morphine and oxycodone. A small, open-label study in 1995 hinted that buprenorphine might have benefit in refractory depression [318]. Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as an adjunctive treatment for MDD. It is a fixed-dose combination of buprenor- phine and samidorphan (a mu opioid receptor agonist). Samidorphan was added to address the abuse and dependence potential of buprenorphine [319]. A 2019 long-term open- label extension study examined the efficacy and adverse effects of adjunctive BUP/SAM [320]. All patients had confirmed MDD and a current MDE lasting 2 to 24 months. Patients were treated with an established antidepressant therapy for a minimum of 8 weeks before receiving sublingual BUP/SAM (2 mg/2 mg) for up to 52 weeks. Safety was assessed via reported adverse events, the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale. Evaluation of efficacy was achieved using MADRS. Of 1,485 patients, 50% completed the study; 11% withdrew due to adverse events (e.g., nausea, headache, constipation, dizziness, somnolence). Drug withdrawal adverse events were infrequent, and euphoria- related adverse events were uncommon. There was no evidence of increased suicidal ideation or behavior. Improvements in MADRS scores were maintained until the end of the study, suggesting durability of antidepressant effect. BUP/SAM was generally well tolerated, with a low risk of abuse [320]. Celecoxib The cyclooxygenase-2 inhibitor celecoxib has demonstrated significant reductions in depressive symptoms compared to placebo as an SSRI add-on in MDD treatment. The decrease in depressive symptoms begins after the first week. However, celecoxib and all other nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with risk of serious cardiovascular events [321].
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