Depression and Suicide _ ______________________________________________________________________
Inositol Myo-inositol is a glucose isomer and an essential component of the phosphatidylinositol second messenger system, which is critically linked to several CNS receptor signaling systems [216; 217; 218; 219]. Randomized controlled trials have found inositol treatment superior in efficacy to placebo in the treatment of major depression, panic disorder, and obsessive- compulsive disorder, and equivalent to fluvoxamine 150 mg/ day in panic disorder [216; 220; 221; 222]. The effective daily dose is 12–18 grams, and inositol at 18 g/day is free of side effects other than loose stools and drowsiness [223]. These results need replication in larger trials but are intriguing. A 2010 study demonstrated that patients with severe depression receiving repetitive transcranial magnetic stimulation therapy showed significantly elevated myo-inositol levels in the left prefrontal cortex; greater elevation correlated with more robust clinical improvement [224]. A small meta-analysis published in 2014 suggests that inositol may be particularly beneficial for patients with premenstrual dysphoric disorder [225]. Myo-inositol is available in nutritional supplement stores but is largely unknown as an antidepressant and anxiolytic in the United States. Folate The use of folate in non-folate-deficient patients with MDD may be most effective as augmentation to SSRIs such as fluox- etine. Persons receiving fluoxetine and folate may have fewer side effects from the SSRI than those receiving fluoxetine alone [22]. Saffron ( Crocus sativus L. ) Saffron is a spice that has been used for the treatment of depres- sion in Persian traditional medicine. Its proposed mechanism involves serotonergic, antioxidant, and anti-inflammatory effects [226]. Several well-designed clinical trials have evaluated the efficacy of saffron 30 mg daily over six to eight weeks in mild-to-moderate depression. The results suggest saffron may be more effective than placebo, at least comparable in efficacy to therapeutic-dose imipramine and fluoxetine in reducing depressive symptoms, and without significant side effects. However, this evidence should ideally be replicated in Western populations [227; 228; 229; 230; 231]. Omega-3 Fatty Acids Evidence suggests omega-3 fatty acids may be beneficial in mood disorders. Treatment efficacy in MDD cannot be determined, but subgroups such as children and pregnant women may show meaningful clinical response. Side effects are minimal [22]. Sleep Deprivation Sleep deprivation therapy involves staying awake through one night and the following day, without any sleep. Although the proposed antidepressant mechanism is poorly understood, clinical trials have consistently shown that around 60% of depressed persons experience moderate improvement to
total remission. However, relapse occurs in 50% to 80% of responders within several days of treatment. Persons with mild depression usually experience a worsening of symptoms [209]. A 2022 systematic review and meta-analysis found no evidence of benefit for sleep deprivation therapy in reducing depressive symptoms [232]. Bright-Light Therapy Bright-light therapy is effective in patients with MDD with season variation (i.e., seasonal affective disorder) and may also be efficacious as monotherapy treatment of MDD without season variation. The correct intensity of light is essential and should be 3,000 to 10,000 lux-hours of white light, adminis- tered at least 30 minutes per day [22]. Results of a systematic review suggest that bright-light therapy at 5,000 lux or greater for periods of 30 minutes or more may be useful as an aug- mentation to standard antidepressant pharmacotherapy for treatment of MDD [233]. Botulinum Toxin A Injection Botulinum toxin A injection is emerging as a novel, effective treatment for MDD. It is widely used in aesthetic medicine to treat glabellar frown lines and has been introduced in the treatment of headaches, muscle pain, and tremor. Patient reports of diminished irritable, depressed, and anxious mood following injection led to its evaluation as treatment of MDD. The first trial of botulinum toxin A (29 units in women, 39–40 units in men) in moderate-to-severe chronic MDD found remission in eight of nine subjects after a single injec- tion in the glabellar region [234]. Functional MRI of patients with MDD shows diminished amygdala responses to negative stimuli after injection of botulinum toxin A, confirming that afferent feedback from the corrugator muscle to the amygdala is reversibly severed [235]. In pooled results from three subsequent randomized controlled trials, single-treatment botulinum toxin A led to significantly greater reductions in mean depression scores (47% vs. 16%), response (52% vs. 8%), and remission (42% vs. 8%) rates than placebo. Age, sex, depression severity, and current antidepres- sant use were not significantly related to response [235]. One small trial found greater response in patients with higher anxious or agitation levels [236]. Symptom reduction is noted around two weeks post-injection and efficacy wears off by three to six months; maintenance injections every three months can be used for relapse prevention. A study from 2021 found that the efficacy of botulinum toxin A was comparable with the antidepressant sertraline for treatment of depression [237]. Use of botulinum toxin A for MDD is currently in phase 3 clinical trials and is off-label [238]. STRATEGIES FOR INADEQUATE RESPONSE TO INITIAL THERAPY If a patient fails to adequately respond to an initial antidepres- sant and/or psychotherapy trial, the clinician should consider adjusting the treatment plan, re-evaluating the initial diagno- sis, and/or optimizing the prescribed therapy. If the patient
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