Family history of alcohol dependence and antidepressant response to an N‐methyl‐D‐aspartate antagonist in bipolar depression

Luckenbaugh DA, Ibrahim L, Brutsche N, Franco‐Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA Jr. Family history of alcohol dependence and antidepressant response to an N‐methyl‐d ‐aspartate antagonist in bipolar depression. Bipolar Disord 2012: 14: 880–887. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. Objectives: Both ketamine and ethanol are N‐methyl‐d ‐aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine’s antidepressant and perceptual effects in individuals with bipolar depression. Methods: A post hoc analysis was conducted on 33 subjects with DSM–IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double‐blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post‐infusion. The primary outcome measure was Montgomery‐Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first‐degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. Results: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. Conclusions: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic‐based therapies for depression.     

(R)‐ and (S)‐ketamine induce differential fMRI responses in conscious rats

(R,S)‐ketamine exerts robust antidepressant effects in patients with depression when given at sub‐anesthetic doses. Each of the enantiomers in this racemic mixture, (R)‐ketamine and (S)‐ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated. Therefore, we investigated the effect of (R,S)‐, (R)‐, and (S)‐ketamine on brain activity by functional MRI (fMRI) in conscious rats and compared these with that of N‐methyl‐D‐aspartate receptor (NMDAR) antagonist MK‐801 (n = 5~7). We also assessed their pharmacokinetic profiles (n = 4) and their behavioral effects (n = 7~9). This pharmacological MRI study revealed a significant positive response to (S)‐ketamine specifically in the cortex, nucleus accumbens and striatum. In contrast, negative fMRI responses were observed in various brain regions after (R)‐ketamine administration. (R,S)‐ketamine, evoked significant positive fMRI responses specifically in the cortex, nucleus accumbens and striatum, and this fMRI response pattern was comparable with that of (S)‐ketamine. MK‐801‐induced similar fMRI response pattern to (S)‐ketamine. The fMRI responses to (S)‐ketamine and MK‐801 showed differential temporal profiles, which corresponded with brain concentration profiles. (S)‐ketamine and MK‐801 significantly increased locomotor activity, while (R)‐ketamine produced no noticeable change. (R,S)‐ketamine tended to increase locomotor activity. Our novel fMRI findings show that (R)‐ketamine and (S)‐ketamine induce completely different fMRI response patterns on rat, and that the response produced by the latter is similar to that elicited by an NMDAR antagonist. Our findings provide insight into the antidepressant mechanism of (R,S)‐ketamine.     

Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Conventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hindered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N-methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast-acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concern. In this review, we focus on the limitations of ketamine, including neurotoxicity, cognitive dysfunction, adverse events associated with mental status, psychotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine (esketamine) and R-ketamine, are also discussed. R-ketamine has greater antidepressant actions than S-ketamine, without ketamine-related side-effects. Future treatment strategies should consider using R-ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term ketamine use.     

Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher—and sTNFR1 levels were significantly lower—in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.     

Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder

Accumulating evidence suggests that N-methyl-d-aspartate receptor (NMDAR) antagonists (e.g. ketamine) may exert rapid antidepressant effects in MDD patients. In the present study, we evaluated the rapid antidepressant effects of ketamine compared with the electroconvulsive therapy (ECT) in hospitalized patients with MDD. In this blind, randomized study, 18 patients with DSM-IV MDD were divided into two groups which received either three intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 min) or ECT on 3 test days (every 48 h). The primary outcome measure was the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS), which was used to rate overall depressive symptoms at baseline, 24 h after each treatment, 72 h and one week after the last (third) ketamine or ECT. Within 24 h, depressive symptoms significantly improved in subjects receiving the first dose of ketamine compared with ECT group. Compared to baseline level, this improvement remained significant throughout the study. Depressive symptoms after the second dose ketamine was also lower than the second ECT. This study showed that ketamine is as effective as ECT in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with the ECT.     

R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.     

Mechanistic Target of Rapamycin–Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model

Background

The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers.

Antidepressant medication exposure and 5‐HT1A autoreceptor binding in major depressive disorder

Objective: We have previously reported higher brain serotonin 1A (5‐HT_1A) autoreceptor binding in antidepressant‐naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5‐HT_1A receptor binding after medication discontinuation. Methods: Positron emission tomography (PET) imaging with the 5‐HT_1A receptor radioligand [¹¹C]WAY‐100635 was performed in 66 individuals with current DSM‐IV MDD to examine relationships between 5‐HT_1A binding and time since most recent antidepressant treatment. All subjects were medication‐free for at least 2 weeks prior to scanning. Thirty‐two additional MDD comparison subjects were antidepressant naïve. Results: No differences in [¹¹C]WAY‐100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [¹¹C]WAY‐100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. Conclusion: These results indicate that any antidepressant‐associated downregulation of 5‐HT_1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness‐related binding levels.     

Rapid-onset antidepressant efficacy of glutamatergic system modulators:The neural plasticity hypothesis of depression

Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However,most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4-8 weeks to reach therapeutic efficacy,a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system,a single dose of the N-methyl-D-aspartate receptor(NMDAR) antagonist ketamine produces rapid(within 2 h) and sustained(over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning,processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine,we review and compare the monoaminergic and glutamatergic antidepressants,with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.     

KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid-acting antidepressant medications. The N-methyl-d -aspartate receptor (NMDA-R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid-acting antidepressant effects of ketamine. This review discusses stress-related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.     

Ketamine administration reduces amygdalo‐hippocampal reactivity to emotional stimulation

Increased amygdala reactivity might lead to negative bias during emotional processing that can be reversed by antidepressant drug treatment. However, little is known on how N‐methyl‐d ‐aspartate (NMDA) receptor antagonism with ketamine as a novel antidepressant drug target might modulate amygdala reactivity to emotional stimulation. Using functional magnetic resonance imaging (fMRI) and resting‐state fMRI (rsfMRI), we assessed amygdalo‐hippocampal reactivity at baseline and during pharmacological stimulation with ketamine (intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h) in 23 healthy subjects that were presented with stimuli from the International Affective Picture System (IAPS). We found that ketamine reduced neural reactivity in the bilateral amygdalo‐hippocampal complex during emotional stimulation. Reduced amygdala reactivity to negative pictures was correlated to resting‐state connectivity to the pregenual anterior cingulate cortex. Interestingly, subjects experienced intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. Our findings suggest that the pharmacological modulation of glutamate‐responsive cerebral circuits, which is associated with a shift in emotional bias and a reduction of amygdalo‐hippocampal reactivity to emotional stimuli, represents an early biomechanism to restore parts of the disrupted neurobehavioral homeostasis in MDD patients. Hum Brain Mapp 37:1941–1952, 2016. © 2016 Wiley Periodicals, Inc .     

Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder

Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is <20 %. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-d-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants.     

Effects of cAMP‐dependent protein kinase activator and inhibitor on in vivo rolipram binding to phosphodiesterase 4 in conscious rats

Rolipram is a selective inhibitor of phosphodiesterase‐4 (PDE4), and positron emission tomography (PET) using [¹¹C]rolipram can monitor the in vivo activity of this enzyme that is part of the cAMP second messenger cascade. cAMP‐dependent protein kinase (PKA) phosphorylates PDE4 and increases both enzyme activity and affinity for rolipram. In the present PET study, we examined effects of PKA modulators in conscious rats on the binding of [¹¹C](R)‐rolipram in comparison to the much less active enantiomer [¹¹C](S)‐rolipram. Unilateral injection of a PKA activator (dibutyryl‐cAMP) and a PKA inhibitor (Rp‐adenosine‐3′,5′‐cyclic monophosphorothioate) into the striatum significantly increased and decreased, respectively, the binding of [¹¹C](R)‐rolipram. These effects were not caused by changes in blood flow or delivery of radioligand to brain, since these agents had no effect on the binding of [¹¹C](S)‐rolipram binding. These results support the value of measuring in vivo [¹¹C](R)‐rolipram binding in brain to assess responses to physiological or pharmacological challenges to the cAMP second messenger system. Synapse 64:172–176, 2010. Published 2009 Wiley‐Liss, Inc.     

Modulation of amygdala reactivity following rapidly acting interventions for major depression

Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.     

Kynurenic acid,by targeting α7 nicotinic acetylcholine receptors,modulates extracellular GABA levels in the rat striatum in vivo

Kynurenic acid (KYNA) is an astrocyte‐derived non‐competitive antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR) and inhibits the NMDA receptor (NMDAR) competitively. The main aim of the present study was to examine the possible effects of KYNA (30 – 1000 nm ), applied locally by reverse dialysis for 2 h, on extracellular GABA levels in the rat striatum. KYNA concentration‐dependently reduced GABA levels, with 300 nm KYNA causing a maximal reduction to ~60% of baseline concentrations. The effect of KYNA (100 nm ) was prevented by co‐application of galantamine (5 μm ), an agonist at a site of the α7nAChR that is very similar to that targeted by KYNA. Infusion of 7‐chlorokynurenic acid (100 nm ), an NMDAR antagonist acting selectively at the glycine_B site of the receptor, affected neither basal GABA levels nor the KYNA‐induced reduction in GABA. Inhibition of endogenous KYNA formation by reverse dialysis of (S)‐4‐(ethylsulfonyl)benzoylalanine (ESBA; 1 mm ) increased extracellular GABA levels, reaching a peak of 156% of baseline levels after 1 h. Co‐infusion of 100 nm KYNA abolished the effect of ESBA. Qualitatively and quantitatively similar, bi‐directional effects of KYNA on extracellular glutamate were observed in the same microdialysis samples. Taken together, the present findings suggest that fluctuations in endogenous KYNA levels, by modulating α7nAChR function, control extracellular GABA levels in the rat striatum. This effect may be relevant for a number of physiological and pathological processes involving the basal ganglia.     

Emerging role of glutamate in the pathophysiology of major depressive disorder

Major depressive disorder (MDD) is a common, chronic, recurrent mental illness that affects millions of individuals worldwide. To date, the monoaminergic systems (serotonin, norepinephrine, and dopamine) have received the most attention in the neurobiology of MDD, and all classes of antidepressants target these monoaminergic systems. Accumulating evidence suggests that the glutamatergic system plays an important role in the neurobiology and treatment of this disease. Some clinical studies have demonstrated that the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant patients with MDD. Here, the author reviews the recent findings on the role of the glutamatergic system in the neurobiology of MDD and in new potential therapeutic targets (NMDA receptors, AMPA receptors, metabotropic glutamate receptors, ceftriaxone, minocycline, N-acetyl-l-cysteine) for MDD.     

Mania associated with antidepressant treatment: comprehensive meta‐analytic review

Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta‐analytic review. Objective: To review available data pertaining to risk of mania–hypomania among bipolar (BPD) and major depressive disorder (MDD) patients with vs. without exposure to antidepressant drugs (ADs) and consider effects of mood stabilizers. Method: Computerized searching yielded 73 reports (109 trials, 114 521 adult patients); 35 were suitable for random effects meta‐analysis, and multivariate‐regression modeling included all available trials to test for effects of trial design, AD type, and mood‐stabilizer use. Results: The overall risk of mania with/without ADs averaged 12.5%/7.5%. The AD‐associated mania was more frequent in BPD than MDD patients, but increased more in MDD cases. Tricyclic antidepressants were riskier than serotonin‐reuptake inhibitors (SRIs); data for other types of ADs were inconclusive. Mood stabilizers had minor effects probably confounded by their preferential use in mania‐prone patients. Conclusion: Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased the risk of mania overall, with little protection by mood stabilizers.     

Pilot dose–response trial of i.v. ketamine in treatment-resistant depression

Objectives. Research studies have reported impressive antidepressant effects with ketamine but significant knowledge gaps remain over the best method of administering ketamine, and the relationships between dose, antidepressant response and adverse effects. Methods. In this pilot dose-finding study, the efficacy and tolerability of ketamine given by rapid intravenous (i.v.) infusion were assessed in a double-blind, placebo-controlled, crossover design, in four subjects with treatment- resistant depression. Each subject received up to four i.v. doses of ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2–5 min, 1 week apart, and one randomly inserted placebo treatment. Results. Three of four subjects achieved antidepressant response (≥ 50% decrease in Montgomery–Asberg Depression Rating Scale scores), two at the minimum 0.1 mg/kg dose, though all relapsed within a week. For two subjects, the greatest improvement occurred at the highest dose received. Rapid infusion over 2 min led to significant adverse psychotomimetic effects which also increased proportionately with ketamine dosage. Conclusions. This is the first trial to present dose–response data of ketamine efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion over 2 min may not be a feasible clinical approach to treatment, given poor tolerability.     

A psychometric evaluation of the clinician‐rated Quick Inventory of Depressive Symptomatology (QIDS‐C16) in patients with bipolar disorder

The clinician‐rated, 16‐item Quick Inventory of Depressive Symptomatology (QIDS‐C₁₆) has been extensively evaluated in patients with major depressive disorder (MDD). This report assesses the psychometric properties of the QIDS‐C₁₆ in outpatients with bipolar disorder (BD, N = 405) and MDD (N = 547) and in bipolar patients in the depressed phase only (BD‐D) (N = 99) enrolled in the Texas Medication Algorithm Project (TMAP) using classical test theory (CTT) and the Samejima graded item response theory (IRT) model. Values of coefficient alpha were very similar in BD, MDD, and BD‐D groups at baseline (α = 0.80–0.81) and at exit (α = 0.82–0.85). The QIDS‐C₁₆ was unidimensional for all three groups. MDD and BD‐D patients (n = 99) had comparable symptom levels. The BD‐D patients (n = 99) had the most, and bipolar patients in the manic phase had the least depressive symptoms at baseline. IRT analyses indicated that the QIDS‐C₁₆ was most sensitive to the measurement of depression for both MDD patients and for BD‐D patients in the average range. The QIDS‐C₁₆ is suitable for use with patients with BD and can be used as an outcome measure in trials enrolling both BD and MDD patients. Copyright © 2009 John Wiley & Sons, Ltd.