Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg(-1)). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

Therapeutic infusions of ketamine: do the psychoactive effects matter?

BACKGROUND: Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This analysis evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24h postinfusion. METHODS: Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions separated by 48h were received: lorazepam (2mg) and two doses of ketamine (0.41mg/kg and 0.71mg/kg, with the former dose always preceding the latter). Infusions were followed within 15min by measures of dissociation (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analogue scale for cocaine craving during cue exposure). RESULTS: Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71mg/kg was associated with significantly higher HMS scores than was the 0.41mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24h postinfusion. CONCLUSIONS: These findings suggest that psychological mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

A pilot study of the effects of chronic paroxetine administration on hippocampal N-acetylaspartate in generalized anxiety disorder.

The neural basis of generalized anxiety disorder (GAD) is poorly characterized. The effect of chronic administration (12 weeks) of paroxetine, a selective serotonin reuptake inhibitor, on N-acetylaspartate (NAA), a marker of neuronal viability, was evaluated in adults with GAD using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T. We hypothesized that, pretreatment abnormalities in hippocampal NAA/creatine (NAA/Cr) would normalize with symptomatic improvement. Nine GAD patients (mean age = 41.7 year; 4 females) received 12 weeks of open-label paroxetine treatment, flexibly dosed up to 60 mg/day. Clinical outcome was assessed with the Hamilton Anxiety Rating Scale (HAM-A). Multislice ( 1)H MRSI scans were performed at unmedicated baseline and following 6 and 12 weeks of treatment. Ten untreated healthy volunteers (HVs) (mean age = 37.1 year; 4 females) received scans at the same intervals. All patients achieved remission (HAM-A

Neuroendocrine predictors of response to intravenous clomipramine therapy for refractory obsessive-compulsive disorder.

The current study examines the neuroendocrine response to intravenous clomipramine (IV CMI) in oral CMI-resistant obsessive-compulsive disorder (OCD) patients on day 1 and day 14 of treatment to identify predictors of response. Forty-four OCD patients with an inadequate response or poorly tolerant to oral CMI were begun at 25 mg IV CMI, increasing to 250 mg by day 10, and continuing on that dose to day 14. On day 1, plasma levels of prolactin (PRL), growth hormone (GH), and cortisol were obtained immediately before the 25 mg IV infusion, and at five 30-minute time points after the infusion. On day 14, hormonal samples were obtained in a similar fashion. Response was assessed by the Clinical Global Impressions (CGI). Low PRL(MAX) to IV CMI and low cortisol levels overall on day 1 were both significantly associated with clinical response at day 14. An overall increase in growth hormone (GH) secretion during the day 14 testing was associated with positive response. A pronounced PRL response to IV CMI on day 14 was exhibited by the nonresponders, whereas a smaller and later but significant increase in PRL was noted in the responders. The findings suggest that in this sample of oral CMI-resistant patients with OCD, neuroendocrine measures derived from pharmacological challenge with IV CMI are capable of distinguishing IV CMI treatment responders from nonresponders. The limitations of IV CMI as a specific probe of serotonin function are discussed.

Neurobiological mechanisms of social anxiety disorder.

OBJECTIVE: The authors critically surveyed several preclinical and clinical neurobiological models of social anxiety disorder. METHOD: The authors reviewed the recent literature regarding three animal models of particular relevance to social anxiety. They then examined the recent literature concerning clinical neurobiological aspects of social anxiety disorder, including the developmental neurobiology of anxiety, the genetics of fear and social anxiety, and challenge and imaging studies. RESULTS: The available animal models are useful paradigms for understanding the features of social subordination stress, attachment behavior, and environmental rearing, but they incompletely account for the known neurobiology of human social anxiety disorder. The clinical neurobiology literature surveyed implicates specific neurotransmitter system abnormalities, most notably of the dopamine system, but largely ignores neurodevelopmental processes and the functional interactions between neurotransmitters. Both heritable factors and environmental stress factors appear to be responsible for the onset of social anxiety disorder. CONCLUSIONS: Social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness that might represent a fully compensated state in adulthood. Future investigations from this perspective are discussed.

Does the difference in the timing of eclosion of the fruit fly Drosophila melanogaster reflect differences in the circadian organization?

The eclosion rhythm of a laboratory population of Drosophila melanogaster was studied under 12h light, 12h dark (LD 12:12) cycles. Although most of the flies were found to eclose just after "lights on" in LD 12:12, termed within gate (WG) flies, a few flies were found to eclose nearly 10h after peak eclosion, termed outside gate (OG) flies. The circadian parameters of the clocks controlling oviposition rhythms in the WG and the OG flies were estimated to understand the cause of such differences in the timing of eclosion. The distribution of the fraction of individual flies exhibiting single, multiple, and no significant period in the WG flies was significantly different from distribution in the OG flies. Compared to the WG flies, more OG flies were found to exhibit oviposition rhythm with multiple periodicity, whereas more WG flies exhibited an oviposition rhythm with a single significant period. The fraction of flies with arrhythmic oviposition was similar in both the WG and the OG flies. Free-running period tau in constant darkness (DD) and the phase angle difference psi in LD 12:12 for the oviposition rhythm of WG and OG flies were significantly different. These results suggest that the differences in the time of eclosion between the flies eclosing within the gate and outside the gate of eclosion are probably due to differences in the circadian system controlling eclosion, which is reflected by the differences in their oviposition rhythm.

Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function.

The search for novel anxiolytics and antidepressants has focused on compounds with the potential to reduce excessive hypothalamic-pituitary-adrenal (HPA) axis activity. L-glutamate, an excitatory neurotransmitter ubiquitously present within the central nervous system, conceivably plays an important role in activating the neural sites involved in stress modulation. Deactivation of the HPA axis by glutamatergic neurotransmission modulation may represent a novel therapeutic approach. Accordingly, the acute intravenous effects of the novel metabotropic (mGlu2/3) agonist LY354740 were tested on bonnet macaques (Macaca radiata) undergoing acute infusions of yohimbine, a noradrenergic stimulant. Dependent measures were the magnitude of the increase of plasma cortisol and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) customarily elicited by yohimbine. Next, the effects of 6 weeks of chronic oral administration of LY354740 on baseline (postcapture) plasma cortisol and MHPG levels in comparison to the identical measure in untreated controls were assessed. Subjects chronically treated with LY354740 received yohimbine infusions which were compared to yohimbine infusions and saline infusions in non-LY354740-treated subjects. Preliminary evidence supports the view that acute LY354740 infusion resulted in a marked diminution of yohimbine-induced stress response, as manifest by a substantial attenuation of cortisol and MHPG response observed in comparison to the saline-treated yohimbine condition. Chronic oral administration of LY354740 led to postcapture baseline cortisol levels which were markedly reduced (approximately 50 percent) in comparison to untreated control subjects; however, there were no significant parallel differences in MHPG levels. Yohimbine infusions elicited an increase in cortisol and MHPG levels in both LY354740-treated and non-LY354740-treated subjects, in comparison to declines in cortisol values observed following vehicle infusions (group X time interaction; P<.0001). Chronic LY354740-treated subjects failed to achieve cortisol levels comparable in range to those of untreated subjects primarily because of their low baseline cortisol levels. In contrast, despite equivalent baselines, yohimbine-induced MHPG values were increased overall in the chronically treated group compared to the saline and yohimbine-alone groups. Thus, LY354740 markedly reduced the acute corticoid and noradrenergic response elicited by yohimbine infusion. Chronic administration of LY354740 appears to present a safe and effective mechanism to markedly down-modulate the HPA axis while retaining noradrenergic responsivity.

Management of treatment-refractory panic disorder.

Treatment resistance remains a relatively common problem in panic disorder (PD) despite the success of the selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) as first-line agents. Factors contributing to medication treatment resistance include inadequacy of trial duration, improper dosage, poor tolerability, noncompliance, and medical and psychiatric comorbidity. Poor tolerability to the SSRIs can frequently be addressed by judicious lowering of the initial dose, with a gradual upward titration. For patients who have not responded to one or more adequate trials of SSRIs, options include combination treatment with a benzodiazepine or tricyclic antidepressant (TCA), augmentation with pindolol, or switching to a different class of medication. The newer antidepressants, particularly venlafaxine XR, seem promising as alternatives, and might be beneficial for the refractory patient with a comorbid mood disorder. Anticonvulsants and olanzapine might be particularly beneficial for the refractory patient with hypomania, irritability, and insomnia, who also has demonstrated acute SSRI hypersensitivity. Experimental therapeutics in refractory panic probably will continue to examine the role of corticotropin releasing factor and glutamate/GABA systems. The role of CBT in the medication refractory patient has been explored, with preliminary suggestions of efficacy.

Biological therapies for obsessive-compulsive disorder.

Two treatments have demonstrated efficacy in OCD, exposure and response (ritual) prevention (EX/RP) and pharmacotherapy with serotonin reuptake inhibitors (SRIs). In this article, which is the third in a three-part series, the authors present an overview of the role of biological treatments for OCD. The evidence for the efficacy of the serotonin reuptake inhibitors (clomipramine and the five selective serotonin reuptake inhibitors "SSRIs" fluvoxamine, fluoxetine, paroxetine, sertraline, and citalopram) as monotherapy for OCD is reviewed. The authors also discuss the rationale for choosing among these agents for specific patients. Research on other types of medication monotherapies for OCD is also discussed. The authors then cover strategies for treatment-resistant OCD, including combining EX/RP and SRI medication treatment, combining clomipramine and an SSRI, use of augmenting medications, and use of intravenous clomipramine. Findings concerning the use of other somatic therapies for treatment-resistant OCD, including electroconvulsive therapy, neurosurgery, plasma exchange/IV immunoglobulin/maintenance antibiotics, and transcranial magnetic stimulation, are also reviewed. Finally, the authors discuss what is known about matching treatments to patients with certain specific symptom clusters, how long to continue maintenance medication treatment, and how to terminate treatment.

Attitudes toward neurosurgical procedures for Parkinson's disease and obsessive-compulsive disorder.

Similar neurosurgical procedures exist for Parkinson's disease (PD) and obsessive-compulsive disorder (OCD). Because PD is seen as a brain disease and OCD as a disease of the mind, neurologists and psychiatrists may be more aware of and more optimistic toward neurosurgery for PD than for OCD. A questionnaire was sent to randomized American Psychiatric Association and American Academy of Neurology members, and 569 of 1,188 eligible members (47.9%) responded. Some 82.8% of the psychiatrists and 27.4% of the neurologists were aware of neurosurgical procedures for OCD, whereas 84.7% of psychiatrists and 99.4% of neurologists were aware of neurosurgery for PD (P < 0.001). Of psychiatrists, 74.1% would refer appropriate patients for OCD neurosurgery, 67.4% for PD neurosurgery (P = 0.15); of neurologists, 25.6% would refer for OCD, 94.3% for PD (P < 0.001). Specialty affected willingness to refer for OCD neurosurgery. Specialty and degree of contact with neurosurgeons affected willingness to refer for PD neurosurgery. There is poor physician awareness of neurosurgical options for OCD compared with PD, as well as a risk-benefit bias against OCD surgery by the neurologists surveyed.

Effects of inhibition of RBC HCO3-/Cl- exchange on CO2 excretion and downstream pH disequilibrium in isolated rat lungs.

To determine the effects of the speed of the erythrocyte membrane chloride shift on pulmonary gas transfer, CO2 exchange and the kinetics of pH equilibration were measured with isolated rat lungs perfused with 20% suspensions of human erythrocytes. The lungs were ventilated with room air, and the inflowing perfusate blood gases were similar to those in mixed venous blood in vivo. All experiments were performed at 37 degrees C. Rates of CO2 excretion were determined by measuring the fraction of CO2 in mixed expired gas in a steady state. The time-course of extracellular pH equilibration in the effluent perfusate was measured in a downstream stopflow pH electrode apparatus. CO2 excretion was reduced by approximately 16% when the lungs were perfused with suspensions containing erythrocytes whose HCO-3/Cl- exchange rates was inhibited, compared with CO2 excretion when the lungs were perfused with normal erythrocyte suspensions. A fall of 0.06 in effluent perfusate extracellular pH was noted during perfusion with inhibited erythrocyte suspensions, in contrast to no observable downstream pH change during perfusion with normal erythrocyte suspensions. These results are in close agreement with the predictions of a theoretical model. Our observations suggest that CO2 transfer in capillary beds will be adversely affected in vivo when the rate of the erythrocyte HCO-3/Cl- exchange is abnormally low. Since a number of commonly used drugs are known to inhibit the chloride shift in human erythrocytes, these findings may have important clinical implications, especially in patients with impaired lung function.