Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation.

OBJECTIVE: Preliminary evidence supports the safety and efficacy of subanesthetic ketamine as an experimental antidepressant, although its effects are often not sustained beyond one week. Studies are lacking that have examined the sustained effects of escalating ketamine doses as augmentation in outpatients with treatment-resistant depression. Therefore, the aims of this study were twofold: (1) to assess the safety and antidepressant efficacy of two-step, repeated-dose ketamine augmentation and (2) to assess the duration of ketamine's antidepressant efficacy as augmentation to ongoing antidepressant pharmacotherapy for 3 months after the final infusion. METHODS: Fourteen patients with treatment-resistant depression were eligible to receive augmentation with six open-label intravenous ketamine infusions over 3 weeks. For the first three infusions, ketamine was administered at a dose of 0.5 mg/kg over 45 minutes; the dose was increased to 0.75 mg/kg over 45 minutes for the subsequent three infusions. The primary outcome measure was response (as measured on Hamilton Depression Rating Scale-28 items). RESULTS: After the completion of three ketamine infusions, 7.1% (1/14) responded; after all six ketamine infusions, 41.7% (5/12) completers responded and 16.7% (2/12) remitted. Intent-to-treat response and remission rates at the end of the final infusion were 35.7% (5/14) and 14.3% (2/14), respectively. However, all but one responder relapsed within 2 weeks after the final infusion. CONCLUSION: Repeated, escalating doses of intravenous ketamine augmentation were preliminarily found to be feasible, efficacious and well tolerated. Interaction with concomitant medications and elevated level of treatment resistance are possible factors for non-response.

Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants.

BACKGROUND: Given the proposed dopaminergic mechanism of low-dose naltrexone (LDN), we examined its efficacy as augmentation for depressive breakthrough on pro-dopaminergic antidepressant regimens. METHODS: 12 adults (67% female, mean age = 45±12) with recurrent DSM-IV major depressive disorder (MDD) on dopaminergic antidepressant regimens (stimulants, dopamine agonists, bupropion [≥300mg/day], aripiprazole [≤2.5mg/day], or sertraline [≥150mg/day]) were randomized to naltrexone 1mg b.i.d. (n=6) or placebo (n=6) augmentation for 3 weeks. RESULTS: All subjects completed the trial. Hamilton Depression Rating Scale (HAM-D-17) scores (primary outcome measure) decreased from 21.2±2.0 to 11.7±7.7 for LDN, from 23.7±2.3 to 17.8±5.9 for placebo (Cohen's d=0.62; p=0.3 between treatment groups). HAM-D-28 scores decreased from 26.2±4.0 to 12.0±9.8 for LDN, from 26.3±2.6 to 19.8±6.6 for placebo (d=1.15; p=0.097). Montgomery-Asberg Depression Rating Scale (MADRS-10 item) scores decreased from 30.4±4.9 to 12.2±8.4 for LDN, from 30.7±4.3 to 22.8±8.5) for placebo (d=1.45; p=0.035). MADRS-15 item scores decreased from 36.6±6.2 to 13.2±8.8 for LDN, from 36.7±4.2 to 26.0±10.0 for placebo (d=1.49; p=0.035). Clinical Global Improvement Scale-Severity (CGI-S) scores decreased from 4.3±0.5 to 3.0±1.1 for LDN, from 4.3±0.5 to 4.0±0.6 for placebo (d=1.22; p=0.064). LIMITATIONS: Small study; restrictions on allowed antidepressants. CONCLUSION: LDN augmentation showed some benefit for MDD relapse on dopaminergic agents. Confirmation in larger studies is needed.

Follicle-stimulating hormone (FSH), current suicidal ideation and attempt in female patients with major depressive disorder.

Current suicidal ideation and attempts are more commonly found in female patients with major depressive disorder (MDD) than in males. However, little is known about the relationship between activity of female reproductive hormones and suicide. The study population consisted of 490 female MDD patients of age ≥18. They were assessed by the Mini-International Neuropsychiatric Interview. At the same visit, we measured blood Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), estradiol, progesterone, Adrenocorticotropic Hormone (ACTH), cortisol, thyroid hormones, and prolactin. Blood FSH showed a significant difference among female MDD patients with suicide attempt, those with ideation, and those without within the previous month. Post-hoc analysis also showed that FSH was significantly lower in MDD patients with suicide attempt and ideation than those without, whereas other hormones showed no differences between those with and without attempt. FSH was negatively associated with current suicidality scores after adjustment for age and education years in all age groups. FSH was significantly lower in those with current suicide ideation or attempt than those without in age 45 years or under, but not in other age groups. In conclusion, blood FSH is significantly lower in female MDD patients with current suicide attempt or ideation than those without, especially in age 45 years or under.

Incentive salience: novel treatment strategies for major depression.

This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates "wanting," or anticipatory reward, rather than "liking," or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or "liking," it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.

Relationship between sleep disturbance and depression, anxiety, and functioning in college students.

BACKGROUND: Sleep disturbance (SD) has complex associations with depression, both preceding and following the onset and recurrence of depression. We hypothesized that students with depressive symptoms with SD would demonstrate a greater burden of comorbid psychiatric symptoms and functional impairment compared to students with depressive symptoms without SD. METHODS: During a mental health screening, 287 undergraduate students endorsed symptoms of depression (Beck Depression Inventory [BDI] ≥ 13) and filled out the following self-report measures: demographic questionnaire, BDI, Anxiety Symptom Questionnaire-intensity and frequency (ASQ), Beck Hopelessness Scale (BHS), Beck Anxiety Inventory (BAI), Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ), and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ). SD was measured using the BDI sleep item #16 dichotomized (score 0: no SD; or score > 0: some SD). RESULTS: Students with depressive symptoms and SD (n = 220), compared to those without SD (n = 67), endorsed significantly more intense and frequent anxiety and poorer cognitive and physical functioning. Students with depressive symptoms with and without SD did not significantly differ in depressive severity, hopelessness, or quality of life. CONCLUSIONS: College students with depressive symptoms with SD may experience a greater burden of comorbid anxiety symptoms and hyperarousal, and may have impairments in functioning, compared to students with depressive symptoms without SD. These findings require replication.

Positive emotion regulation in emotional disorders: a theoretical review.

Conceptualizations of emotion regulation have led to the identification of cognitive and behavioral regulatory abnormalities that contribute to the development and maintenance of emotional disorders. However, existing research on emotion regulation in anxiety and mood disorders has primarily focused on the regulation of negative emotions rather than positive emotions. Recent findings indicate that disturbances in positive emotion regulation occur across emotional disorders, and may be a generative target for treatment research. The aims of this paper are to: 1. Present a transdiagnostic model of positive emotion disturbances in emotional disorders; 2. Review evidence for disturbances in positive emotion regulation in emotional disorders across categories of emotion regulation; and 3. Propose treatment strategies that may address these disturbances.

Antidepressant effects on emotional temperament: toward a biobehavioral research paradigm for major depressive disorder.

BACKGROUND: Given the limited efficacy of current pharmacotherapy for major depressive disorder (MDD) and the historical decline in antidepressant development, there is increasing clinical urgency to develop more effective treatments. OBJECTIVES: To synthesize findings from clinical psychology and affective neuroscience related to the construct of emotional temperament; to examine the effects of antidepressants on the temperament dimensions of positive (PA) and negative affectivity (NA); and to propose a biobehavioral research paradigm for the treatment of MDD. METHODS: We begin with an introduction to PA and NA, which emphasizes their construct development, historical context, and relevance to psychopathology. We then review studies of antidepressant effects on PA and NA, and explore two related hypotheses: (1) Cause-correction: The antidepressant response may fundamentally occur through changes in emotional temperament, with subsequent spread to syndrome or symptom changes; (2) preferential effects: Antidepressants with different mechanisms of action may have preferential effects on PA or NA. RESULTS: Preliminary findings appear to support the cause-correction hypothesis; there is insufficient clinical evidence to support the preferential effects hypothesis. CONCLUSIONS: PA and NA are biologically based temperament dimensions, which modulate emotional, motivational, and behavioral responses to positive and negative incentives. They can be altered by antidepressants, and may independently contribute to depression improvement. In addition, the distinct biobehavioral features of PA and NA suggest that combined pharmacological and cognitive-behavioral treatments targeting these dimensions may have specific, and perhaps, synergistic antidepressant effects.

Phenytoin toxicity secondary to an oxcarbazepine-phenytoin 2C19 interaction.

BACKGROUND: Polytherapy is common in the management of bipolar disorder, as are the side effects associated with this treatment strategy. OBJECTIVE: The authors review the literature on drug-drug interactions involving oxcarbazepine and identify specific mechanisms that may have clinical importance. METHOD: The authors provide a case report of a patient who developed phenytoin toxicity associated with an oxcarbazepine-phenytoin interaction. RESULTS: Co-administration of phenytoin and oxcarbazepine resulted in toxic levels of phenytoin. Therefore, the patient's daily dosage of oxcarbazepine and phenytoin were reduced. DISCUSSION: Although oxcarbazepine is an inducer of the 3A4 isoenzyme, it acts as an inhibitor of the 2C19 isoenzyme, and it can raise levels of other agents, for example, phenytoin, that are also metabolized by this isoenzyme.