Deborah S. Cowley

Psychedelic effects of ketamine in healthy volunteers. Relationship to steady-state plasma concentrations

Background Ketamine has been associated with a unique spectrum of subjective “psychedelic” effects in patients emerging from anesthesia. This study quantified these effects of ketamine and related them to steady‐state plasma concentrations. Methods Ketamine or saline was administered in a single‐blinded crossover protocol to 10 psychiatrically healthy volunteers using computer‐assisted continuous infusion. A stepwise series of target plasma concentrations, 0, 50, 100, 150, and 200 ng/ml were maintained for 30 min each. After 20 min at each step, the volunteers completed a visual analog (VAS) rating of 13 symptom scales. Peripheral venous plasma ketamine concentrations were determined after 28 min at each step. One hour after discontinuation of the infusion, a psychological inventory, the hallucinogen rating scale, was completed. Results The relation of mean ketamine plasma concentrations to the target concentrations was highly linear, with a correlation coefficient of R = 0.997 (P = 0.0027). Ketamine produced dose‐related psychedelic effects. The relation between steady‐state ketamine plasma concentration and VAS scores was highly linear for all VAS items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P < 0.024 to P <0.0005). Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N‐dimethyltryptamine, an illicit LSD‐25‐like drug. Conclusions Subanesthetic doses of ketamine produce psychedelic effects in healthy volunteers. The relation between steady‐state venous plasma ketamine concentrations and effects is highly linear between 50 and 200 ng/ml.

DSM-III-R personality disorders in a mood and anxiety disorders clinic: prevalence, comorbidity, and clinical correlates.

This study examined the prevalence, comorbidity, and clinical correlates of personality disorders in an outpatient sample (N = 352) with anxiety and depression. Subjects were diagnosed using the Structured Clinical Interview for DSM-III-R (SCID) on Axes I and II, and they also completed interview and self-report measures of symptoms. Subjects with a personality disorder were less likely to be married, more likely to be single or divorced, had lower family incomes, had more severe symptoms of both anxiety and depression, and had a greater number of lifetime Axis I diagnoses. Subjects with dysthymic and bipolar disorders were more likely, and subjects with panic disorder uncomplicated by agoraphobia were less likely to have a personality disorder compared to the rest of the sample. The most prevalent personality disorders were Avoidant, Obsessive-Compulsive, Paranoid, and Borderline. Paranoid co-occurred with Narcissistic, and Borderline co-occurred with Histrionic personality disorder significantly more often than chance and base rates would predict.

Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?

Evidence from histological and pharmacological challenge studies indicates that N-methyl-D-aspartate (NMDA) receptor hypofunction may play an important role in the pathophysiology of schizophrenia. Our goal was to characterize effects of NMDA hypofunction further, as related to schizophrenia-associated neuropsychological impairment. We administered progressively higher doses of ketamine (target plasma concentrations of 50, 100, 150, and 200 ng/ml) to 10 psychiatrically healthy young men in a randomized, single-blind, placebo-controlled design and assessed oculomotor, cognitive, and symptomatic changes. Mean ketamine plasma concentrations approximated target plasma concentrations at each infusion step. Verbal recall, recognition memory, verbal fluency, pursuit tracking, visually guided saccades, and fixation all deteriorated significantly during ketamine infusion; lateral gaze nystagmus explained some, but not all, of the smooth pursuit abnormalities. We concluded that ketamine induces changes in recall and recognition memory and verbal fluency reminiscent of schizophreniform psychosis. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities characteristic of schizophrenia. These findings help delineate the similarities and differences between schizophreniform and NMDA–blockade-induced cognitive and oculomotor abnormalities.

Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder

BACKGROUND Although experimental induction of panic by infusion of 0.5 mol/L sodium lactate in persons with panic disorder was described three decades ago, the mechanism underlying this observation remains unclear. Here we asked if the rapid administration of the large sodium load contained in the 0.5-mol/L sodium lactate infusion might be involved in panic induction. METHODS We compared in panic disorder and healthy subjects behavioral, electrolyte, endocrine, and acid-base responses to three double-blind randomly ordered equal volume 20-min infusions: 0.5 mol/L sodium lactate, hypertonic saline (3% sodium chloride), and normal saline placebo. RESULTS Sodium lactate (0.5 mol/L) and hypertonic saline produced the same high incidence of panic and equivalent increases in panic symptoms, serum sodium, and plasma vasopressin in the panic disorder subjects. Neither hypertonic infusion increased cortisol or adrenocorticotropin. No normal subject experienced panic in any condition. The 0.5-mol/L sodium lactate infusion induced alkalosis, whereas hypertonic saline and normal saline induced a mild acidosis. CONCLUSIONS Hypertonic sodium solution containing either chloride or lactate anion induces panic in panic disorder. The large sodium loads delivered by hypertonic saline and 0.5 mol/L sodium lactate may be involved in the mechanism of panic induction.

Relationships between Neuropsychological and Oculomotor Measures in Schizophrenia Patients and Normal Controls

Establishing the relationship between oculomotor and neuropsychological impairments might facilitate a more coherent description of schizophrenia-associated neurocognitive deficits. Therefore, we assessed several aspects of neuropsychological and oculomotor function in 25 medicated schizophrenia patients and 24 age-matched controls. Neuropsychological tasks included the Wisconsin Cart Sort Test (WCST), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test, and finger tapping speed. Oculomotor functions assessed included smooth pursuit, initiation of smooth pursuit, predictive pursuit, fixation, visually guided saccades, remembered saccades, and antisaccades. Among the schizophrenia patients, predictive pursuit performance correlated significantly with finger tapping (dominant hand), TMT (both parts), and one WCST measure (categories completed). The only other significant correlation among the schizophrenia patients was between antisaccade performance and part A of the TMT. Perseverative errors during the WCST and antisaccade performance were the only measures significantly correlated among the normals. Closely related neurocognitive deficits may be responsible for impairments in TMT, WCST, predictive pursuit, and antisaccade performance in schizophrenia.

Nefazodone treatment of major Depression in alcohol-dependent patients : A double-blind, placebo-controlled trial

Depression is the most common comorbid psychiatric illness in patients with alcohol dependence. This double-blind study tested the efficacy of nefazodone versus placebo for the treatment of depression in actively drinking alcohol-dependent patients who were also participating in weekly group treatment for alcoholism. Sixty-four subjects with major depression disorder and alcohol dependence with a history of at least one prior episode of depression when not drinking were randomly assigned to receive 12 weeks of either nefazodone or placebo and participated in a weekly psychoeducational group on alcoholism. Subjects were assessed every 2 weeks for depression, anxiety, side effects, and drinking frequency. Subjects taking nefazodone were significantly more likely to complete the study (62%) than those taking placebo (34%). Analyses of covariance using drinks per week as a time-dependent covariate showed lower Hamilton Rating Scale for Depression scores at week 8 for end-point analysis and at weeks 8 and 12 for completers. The endpoint analysis demonstrated a significantly greater response in the nefazodone group (48%) than in the placebo group (16%). Both groups showed a similarly significant decrease in the average number of alcoholic drinks consumed per day over the course of the study. Although the number of adverse effects was significantly greater for the nefazodone group, there were no severe adverse events, and nefazodone was well tolerated. Nefazodone is a safe and effective antidepressant to use in a population of alcohol-dependent patients with depression who have a high degree of comorbidity. Nefazodone treatment was superior to placebo in alleviating depression in these patients but did not add any advantage over the psychoeducational group in terms of drinking outcomes.

The relationship between anxiety and depression: A clinical comparison of generalized anxiety disorder, dysthymic disorder, panic disorder, and major depressive disorder

This study examined the relationship between the chronic disorders, generalized anxiety disorder (GAD) and dysthymic disorder (DD), and the more acute disorders, panic disorder (PD) and major depressive disorder (MDD) in 110 psychiatric outpatients with diagnoses of either PD, MDD, GAD, or DD. Pure, mixed, and early-/late-onset forms of the chronic disorders were compared with each other and then with PD and MDD on clinical measures and psychiatric history. Minimal differences were found between pure GAD and mixed GAD or between pure DD and mixed DD. The chronic disorders, DD and GAD, had distinct clinical symptom profiles when compared with each other and appeared more closely related to their parent disorders than to each other. However, despite these similarities, there were significant differences between DD and MDD in contrast to the minimal differences between GAD and PD, providing less support for GAD as a valid diagnostic category separate from PD. Comparisons of early-/late-onset DD and GAD showed more severe symptoms in late-onset DD, in contrast to more severe symptoms in early-onset GAD. These varying patterns of symptom severity may warrant study for further syndromal delineation.

Biological markers in panic states: Lactate-induced panic and mitral valve prolapse

Anxious patients, and more specifically, patients experiencing panic attacks, are thought to have a significant biological component to their illness. This study looks at two promising biological markers associated with this patient population-mitral valve prolapse and lactate-induced panic. We present our findings, which further characterize clinical and biological aspects of these two markers.

Benzodiazepine pharmacodynamics: utility of eye movement measures

The utility of several measures of saccadic and smooth pursuit eye movements as benzodiazepine pharmacodynamic measures was explored in 24 psychiatrically and medically healthy control subjects. Measures of sedation and memory impairment were also included. Subjects received four logarithmically increasing doses of intravenous diazepam at 15-min intervals on 1 day resulting in monotonically increasing plasma diazepam levels, and placebo on another day in random order 1 week apart. Measures were collected twice at baseline, once after each dose of diazepam/placebo and twice more, 15 and 30 min after the last dose. Peak saccadic velocity and smooth pursuit gain showed the greatest overall and dose-dependent drug effect among eye movement measures. Although effect sizes at the highest dose for memory impairment and self-rated sedation were comparable to these two measures, reliability (i.e., placebo-day fluctuation) with these measures was considerably poorer. Loglinear pharmacodynamic modeling was used to calculate the effective dose (ED30) or concentration (EC30) required to reduce saccadic velocity or pursuit gain by 30%. Almost all (23/24) subjects had linear and easily interpretable plots for saccadic velocity, while a majority (19/24) of subjects had interpretable plots for smooth pursuit gain. The distribution of ED30 and EC30 values showed a wide range of sensitivities to diazepam. These findings suggest that saccadic velocity and smooth pursuit gain are sensitive, reliable, quantitative benzodiazepine pharmacodynamic measures.

Personality and benzodiazepine sensitivity in anxious patients and control subjects

Cloninger has recently proposed a model of personality variability that is based on three independent heritable traits of harm avoidance, novelty seeking, and reward dependence, each of which is thought to be mediated by a separate neurochemical and neuroanatomic mechanism. The current study tested hypotheses generated on the basis of this theory in anxious patients and control subjects. Eighteen patients with panic disorder, 12 patients with generalized anxiety disorder, and 21 control subjects underwent both personality testing and assessment of their sensitivity to diazepam, as measured by slowing of saccadic eye movement velocity. As expected, anxious patients displayed higher harm avoidance scores than controls. Although an inverse correlation between harm avoidance and benzodiazepine sensitivity was predicted, no relationship between these variables was found in any diagnostic group. However, a significant correlation was found between novelty-seeking scores and sensitivity to diazepam. This finding, although not predicted by Cloningers theory, is consistent with prior preclinical and human studies.