_______________________________________________________________________ Depression and Suicide
Aripiprazole has been found superior to switching anti- depressants in patients with current depressive episodes, despite adequate antidepressant dosage, and in patients with antidepressant non-response [258]. Brexpiprazole is another atypical antipsychotic effective as add-on therapy; aripiprazole and brexpiprazole are approved by the FDA as augmentation therapies in MDD [64; 150; 192]. Although well tolerated, brexpiprazole does not appear to offer a statistically significant benefit over placebo as an adjunctive treatment [259]. The evidence base for lithium and triiodothyronine shows efficacy, but mainly involves studies that combined these agents with TCAs or MAOIs [150]. Methylphenidate has mostly shown mixed results in reducing depressive symptoms [260; 261]. Modafinil has not shown consistent efficacy in core MDD symptoms, but it has demonstrated improvements in symp- toms/dimensions of psychopathology highly relevant to patient function, including fatigue, apathy, anhedonia, amotivation, and cognitive impairment [262]. Adverse effects have not dif- fered from placebo [159; 263]. Lisdexamfetamine, a dextroamphetamine prodrug, showed some evidence of efficacy as an adjunctive agent for partial SSRI responders in two placebo-controlled randomized con- trolled trials [182; 264]. Pramipexole is a dopamine receptor agonist and a standard therapeutic in Parkinson disease. Preliminary evidence shows some benefit in patients with MDD lacking response to multiple antidepressant regimens [265; 266]. The optimal duration of add-on therapy is not known, but it seems prudent that patients who are tolerating treatment and achieving therapeutic objectives should continue for at least 6 to 12 months with ongoing reassessment, with indefinite continuation for many [150]. TREATMENT-RESISTANT DEPRESSION Most definitions of treatment response compare changes in depression rating scale scores between pre-treatment and follow-up. Standardized rating scales such as the MADRS and HAM-D are widely used to quantify treatment response [249]. As discussed, the definition of antidepressant response falls into four categories [21; 111]: • Remission: The absence of depressive symptoms or minimal symptoms (HAM-D score ≤7) • Response: A 50% or greater reduction in symptoms • Partial response: A 25% to 50% reduction in symptoms • Nonresponse: The absence of meaningful response (symptom reduction ≤25%)
Standard antidepressants fail to produce adequate response in 30% to 50% and remission in up to 70% of patients with MDD [267; 268; 269]. Partial response, instead of full remis- sion, leaves patients with impairing residual symptoms and high risk of relapse. Each relapse increases symptom severity, decreases treatment response, and heightens risk of treatment- resistant MDD [270]. Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Contributors to treatment-resistant depression include ill- ness severity, medical and psychiatric comorbidity, and the limitations of FDA-approved drug options. The definition of treatment resistance lacks consensus, but the most common definition is inadequate response to two or more antidepres- sants. This does not consider adjunctive strategies or distin- guish patients with partial versus non-response [158; 180]. In addition to augmentation strategies discussed, a diverse and growing range of interventions are available as options for treatment-resistant depression. Most engage novel thera- peutic targets.
OPTIONS FOR TREATMENT-RESISTANT DEPRESSION Bright-Light Therapy
As mentioned, use of bright-light therapy for treatment of major depression with a seasonal specifier (seasonal affective disorder) is well established [271; 272]. There is also evidence supporting its use for additional types of depressive symptom patterns, including non-seasonal depression, milder variations of seasonal depressive patterns, and depression in pregnant and postpartum women [273; 274; 275]. Bright-light therapy may quicken and enhance the effects of antidepressants [276]. The interaction between light intensity and duration of expo- sure requires two hours daily with 2,500 lux, one hour with 5,000 lux, and 30 minutes daily with 10,000 lux for efficacy [277]. Light therapy must also use equipment that eliminates ultraviolet frequencies. Neurostimulation Therapies The limitations of standard antidepressants, frequent treat- ment resistance, and the paradigm shift in psychiatry away from specific neurotransmitter focus and toward an integrative neural network perspective has prompted the development of novel depression treatment approaches, such as neurostimula- tion therapy. Neurostimulation therapies include a range of techniques that deliver electrical or magnetic stimulation to specific brain region targets for the treatment of refractory psychiatric and pain conditions. Neurostimulation efficacy in neurologic disorders led to their introduction in psychiatry. In addition to ECT, several others are now FDA-approved for use in MDD and related disorders.
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