Ralitza Gueorguieva

The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis.

Recent advances in the understanding of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis. In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral, cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9-tetrahydrocannabinol (Δ-9-THC) were characterized in 22 healthy individuals, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also collected. Δ-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that Δ-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses. These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders.

Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction

BACKGROUND Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. METHODS In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. RESULTS Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. CONCLUSIONS Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

Riluzole Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: An Open-Label Trial

BACKGROUND Most patients with obsessive-compulsive disorder (OCD) show only partial reduction of symptoms with standard therapy. Recent imaging data suggests glutamatergic dysfunction in the corticostriatal pathway in OCD. We investigated the efficacy of augmentation therapy with riluzole, a glutamate-modulating agent, in treatment-resistant OCD. METHODS Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy. Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A) scores were obtained weekly. RESULTS Thirteen treatment-resistant OCD patients received riluzole 50 mg twice a day. Y-BOCS scores improved significantly over time. Of 13 patients, 7 (54%) demonstrated a >35% reduction in Y-BOCS scores, and 5 (39%) were categorized as treatment responders. HAM-D and HAM-A scores for the group also significantly improved over time. Riluzole was well tolerated with no serious adverse effects noted. CONCLUSIONS Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD.

Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample.

BACKGROUND Auditory hallucinations are often resistant to treatment and can produce significant distress and behavioral difficulties. A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory hallucinations following 1-hertz left temporoparietal repetitive transcranial magnetic stimulation (rTMS) compared to sham stimulation. Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention. METHODS Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham stimulation. A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. RESULTS Hallucination Change Score was more improved for rTMS relative to sham stimulation (p = .008) as was the Clinical Global Impressions Scale (p = .0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p = .0014) and was a moderator of rTMS effects (p = .008). There was no evidence of neurocognitive impairment associated with rTMS. CONCLUSIONS Left temporoparietal 1-hertz rTMS warrants further study as an intervention for auditory hallucinations. Data suggest that this intervention selectively alters neurobiological factors determining frequency of these hallucinations.

Extracellular metabolites in the cortex and hippocampus of epileptic patients

Interictal brain energy metabolism and glutamate–glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero‐flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate–glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies. Ann Neurol 2005;57:226–235

Blunted Psychotomimetic and Amnestic Effects of |[Delta]|-9-Tetrahydrocannabinol in Frequent Users of Cannabis

Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Δ-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Δ-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of ‘high’; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Δ-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.

Investigating the behavioral and self-report constructs of impulsivity domains using principal component analysis.

Impulsivity, often defined as a human behavior characterized by the inclination of an individual to act on urge rather than thought, with diminished regard to consequences, encompasses a range of maladaptive behaviors, which are in turn affected by distinct neural systems. Congruent with the above definition, behavioral studies have consistently shown that the underlying construct of impulsivity is multidimensional in nature. However, research to date has been inconclusive regarding the different domains or constructs that constitute this behavior. In addition there is also no clear consensus as to whether self-report and laboratory based measures of impulsivity measure the same or different domains. This study aimed to: (i) characterize the underlying multidimensional construct of impulsivity using a sample with varying degrees of putative impulsivity related to substance misuse, including subjects who were at-risk of substance use or addicted (ARA), and (ii) assess relationships between self-report and laboratory measures of impulsivity, using a principal component-based factor analysis. In addition, our supplementary goal was to evaluate the structural constructs of impulsivity within each group separately (healthy and ARA). We used five self-report measures (Behavioral Inhibition System/Behavioral Activation System, Barratt Impulsivity Scale-11, Padua Inventory, Zuckerman Sensation Seeking Scale, and Sensitivity to Punishment and Sensitivity to Reward Questionnaire) and two computer-based laboratory tasks (Balloon Analog Risk Task and the Experiential Discounting Task) to measure the aspects of impulsivity in a total of 176 adult subjects. Subjects included healthy controls (n = 89), nonalcoholic subjects with family histories of alcoholism (family history positive; n = 36) and both former (n = 20) and current (n = 31) cocaine users. Subjects with a family history of alcoholism and cocaine abusers were grouped together as ‘at-risk/addicted’ (ARA) to evaluate our supplementary goal. Our overall results revealed the multidimensional nature of the impulsivity construct as captured optimally through a five-factor solution that accounted for nearly 70% of the total variance. The five factors/components were imputed as follows ‘Self-Reported Behavioral Activation’, ‘Self-Reported Compulsivity and Reward/Punishment’, ‘Self-Reported Impulsivity’, ‘Behavioral Temporal Discounting’, and ‘Behavioral Risk-Taking’. We also found that contrary to previously published reports, there was significant overlap between certain laboratory and self-report measures, indicating that they might be measuring the same impulsivity domain. In addition, our supplemental analysis also suggested that the impulsivity constructs were largely, but not entirely the same within the healthy and ARA groups.

Cognitive-behavioral therapy, behavioral weight loss, and sequential treatment for obese patients with binge-eating disorder: a randomized controlled trial.

OBJECTIVE Cognitive-behavioral therapy (CBT) is the best established treatment for binge-eating disorder (BED) but does not produce weight loss. The efficacy of behavioral weight loss (BWL) in obese patients with BED is uncertain. This study compared CBT, BWL, and a sequential approach in which CBT is delivered first, followed by BWL (CBT + BWL). METHOD 125 obese patients with BED were randomly assigned to 1 of the 3 manualized treatments delivered in groups. Independent assessments were performed posttreatment and at 6- and 12-month follow-ups. RESULTS At 12-month follow-up, intent-to-treat binge-eating remission rates were 51% (CBT), 36% (BWL), and 40% (CBT + BWL), and mean percent BMI losses were -0.9, -2.1, and 1.5, respectively. Mixed-models analyses revealed that CBT produced significantly greater reductions in binge eating than BWL through 12-month follow-up and that BWL produced significantly greater percent BMI loss during treatment. The overall significant percent BMI loss in CBT + BWL was attributable to the significant effects during the BWL component. Binge-eating remission at major assessment points was associated significantly with greater percent BMI loss cross-sectionally and prospectively (i.e., at subsequent follow-ups). CONCLUSIONS CBT was superior to BWL for producing reductions in binge eating through 12-month follow-up, while BWL produced statistically greater, albeit modest, weight losses during treatment. Results do not support the utility of the sequential approach of providing BWL following CBT. Remission from binge eating was associated with significantly greater percent BMI loss. Findings support BWL as an alternative treatment option to CBT for BED.

Preliminary evidence for medication effects on functional abnormalities in the amygdala and anterior cingulate in bipolar disorder

RationaleAbnormal amygdala and frontocortical responses to emotional stimuli are implicated in bipolar disorder (BD) and have been proposed as potential treatment targets.ObjectivesThe aim of this study was to investigate amygdala and frontocortical responses to emotional face stimuli in BD and the influences of mood-stabilizing medications on these responses.MethodsFunctional magnetic resonance imaging was performed while 17 BD participants (5 unmedicated) and 17 healthy comparison (HC) participants viewed faces with happy, sad, fearful, or neutral expressions.ResultsThe group by stimulus-condition interaction was significant (p<0.01) for amygdala activation, with the greatest effects in the happy face condition. Relative to HC, amygdala increases were greater in unmedicated BD, but lower in medicated BD. Rostral anterior cingulate (rAC) activation was decreased in unmedicated BD compared to HC; however, BD participants taking medication demonstrated rAC activation similar to HC participants.ConclusionsAlthough the sample sizes were small, these preliminary results suggest that BD is associated with increased amygdala and decreased rAC response to emotional faces. The findings also provide preliminary evidence that mood-stabilizing medications may reverse abnormalities in BD in the response of an amygdala–frontal neural system to emotional stimuli.

Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study.

OBJECTIVE Most previous studies of the incidence of tardive dyskinesia with atypical antipsychotics compared with conventional antipsychotics have not had tardive dyskinesia as their primary focus. The current study aimed to compare the incidence of tardive dyskinesia with atypical vs conventional antipsychotics using methods similar to those from a previous prospective cohort study at our site in the 1980s. METHOD Three hundred fifty-two initially tardive dyskinesia-free psychiatric outpatients (diagnosed at baseline using the Structured Clinical Interview for DSM-IV) were examined for a new diagnosis of tardive dyskinesia (using the Abnormal Involuntary Movement Scale and Glazer-Morgenstern criteria) every 6 months for up to 4 years at a community mental health center. At baseline, subjects were receiving conventional antipsychotics only (23%), atypicals only (64%), or both (14%). Only 26 subjects had never received conventional antipsychotics. Baseline evaluations were conducted from November 2000 through May 2003. Follow-ups were conducted through February 2005. RESULTS Compared with subjects treated with conventional antipsychotics alone since the previous visit, the adjusted tardive dyskinesia incidence rate-ratio for subjects treated with atypical antipsychotics alone was 0.68 (95% CI, 0.29-1.64). The incidence and prevalence of tardive dyskinesia was similar to previous findings at this site in the 1980s. CONCLUSIONS The incidence of tardive dyskinesia with recent exposure to atypical antipsychotics alone was more similar to that for conventional antipsychotics than in most previous studies. Despite high penetration of atypical antipsychotics into clinical practice, the incidence and prevalence of tardive dyskinesia appeared relatively unchanged since the 1980s. Clinicians should continue to monitor for tardive dyskinesia, and researchers should continue to pursue efforts to treat or prevent it.