First-Episode Services for Psychotic Disorders in the U.S. Public Sector: A Pragmatic Randomized Controlled Trial.

OBJECTIVE: This study sought to determine the effectiveness of a comprehensive first-episode service, the clinic for Specialized Treatment Early in Psychosis (STEP), in an urban U.S. community mental health center by comparing it with usual treatment. METHODS: This pragmatic randomized controlled trial enrolled 120 patients with first-episode psychosis within five years of illness onset and 12 weeks of antipsychotic exposure. Referrals were mostly from inpatient psychiatric units, and enrollees were randomly allocated to STEP or usual treatment. Main outcomes included hospital utilization (primary); the ability to work or attend age-appropriate schooling-or to actively seek these opportunities (vocational engagement); and general functioning. Analysis was by modified intent to treat (excluding only three who withdrew consent) for hospitalization; for other outcomes, only data for completers were analyzed. RESULTS: After one year, STEP participants had less inpatient utilization compared with those in usual treatment: no psychiatric hospitalizations, 77% versus 56% (risk ratio [RR]=1.38, 95% confidence interval [CI]=1.08-1.58); mean hospitalizations, .33±.70 versus .68±.92 (p=.02); and mean bed-days, 5.34±13.53 versus 11.51±15.04 (p=.05). For every five patients allocated to STEP versus usual treatment, one additional patient avoided hospitalization over the first year (number needed to treat=5; CI=2.7-26.5). STEP participants also demonstrated better vocational engagement (91.7% versus 66.7%; RR=1.40, CI=1.18-1.48) and showed salutary trends in global functioning measures. CONCLUSIONS: This trial demonstrated the feasibility and effectiveness of a U.S. public-sector model of early intervention for psychotic illnesses. Such services can also support translational research and are a relevant model for other serious mental illnesses.

Resting state functional connectivity predicts neurofeedback response.

Tailoring treatments to the specific needs and biology of individual patients-personalized medicine-requires delineation of reliable predictors of response. Unfortunately, these have been slow to emerge, especially in neuropsychiatric disorders. We have recently described a real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback protocol that can reduce contamination-related anxiety, a prominent symptom of many cases of obsessive-compulsive disorder (OCD). Individual response to this intervention is variable. Here we used patterns of brain functional connectivity, as measured by baseline resting-state fMRI (rs-fMRI), to predict improvements in contamination anxiety after neurofeedback training. Activity of a region of the orbitofrontal cortex (OFC) and anterior prefrontal cortex, Brodmann area (BA) 10, associated with contamination anxiety in each subject was measured in real time and presented as a neurofeedback signal, permitting subjects to learn to modulate this target brain region. We have previously reported both enhanced OFC/BA 10 control and improved anxiety in a group of subclinically anxious subjects after neurofeedback. Five individuals with contamination-related OCD who underwent the same protocol also showed improved clinical symptomatology. In both groups, these behavioral improvements were strongly correlated with baseline whole-brain connectivity in the OFC/BA 10, computed from rs-fMRI collected several days prior to neurofeedback training. These pilot data suggest that rs-fMRI can be used to identify individuals likely to benefit from rt-fMRI neurofeedback training to control contamination anxiety.

Glycine treatment of the risk syndrome for psychosis: report of two pilot studies.

Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium-to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.

Does maintenance CBT contribute to long-term treatment response of panic disorder with or without agoraphobia? A randomized controlled clinical trial.

OBJECTIVE: We examined the possibility that maintenance cognitive behavior therapy (M-CBT) may improve the likelihood of sustained improvement and reduced relapse in a multi-site randomized controlled clinical trial of patients who met criteria for panic disorder with or without agoraphobia. METHOD: Participants were all patients (N = 379) who first began an open trial of acute-phase CBT. Patients completing and responding to acute-phase treatment were randomized to receive either 9 monthly sessions of M-CBT (n = 79) or assessment only (n = 78) and were then followed for an additional 12 months without treatment. RESULTS: M-CBT produced significantly lower relapse rates (5.2%) and reduced work and social impairment compared to the assessment only condition (18.4%) at a 21-month follow-up. Multivariate Cox proportional hazards models showed that residual symptoms of agoraphobia at the end of acute-phase treatment were independently predictive of time to relapse during 21-month follow-up (hazards ratio = 1.15, p < .01). CONCLUSIONS: M-CBT aimed at reinforcing acute treatment gains to prevent relapse and offset disorder recurrence may improve long-term outcome for panic disorder with and without agoraphobia.

Real-time fMRI biofeedback targeting the orbitofrontal cortex for contamination anxiety.

We present a method for training subjects to control activity in a region of their orbitofrontal cortex associated with contamination anxiety using biofeedback of real-time functional magnetic resonance imaging (rt-fMRI) data. Increased activity of this region is seen in relationship with contamination anxiety both in control subjects and in individuals with obsessive-compulsive disorder (OCD), a relatively common and often debilitating psychiatric disorder involving contamination anxiety. Although many brain regions have been implicated in OCD, abnormality in the orbitofrontal cortex (OFC) is one of the most consistent findings. Furthermore, hyperactivity in the OFC has been found to correlate with OCD symptom severity and decreases in hyperactivity in this region have been reported to correlate with decreased symptom severity. Therefore, the ability to control this brain area may translate into clinical improvements in obsessive-compulsive symptoms including contamination anxiety. Biofeedback of rt-fMRI data is a new technique in which the temporal pattern of activity in a specific region (or associated with a specific distributed pattern of brain activity) in a subject's brain is provided as a feedback signal to the subject. Recent reports indicate that people are able to develop control over the activity of specific brain areas when provided with rt-fMRI biofeedback. In particular, several studies using this technique to target brain areas involved in emotion processing have reported success in training subjects to control these regions. In several cases, rt-fMRI biofeedback training has been reported to induce cognitive, emotional, or clinical changes in subjects. Here we illustrate this technique as applied to the treatment of contamination anxiety in healthy subjects. This biofeedback intervention will be a valuable basic research tool: it allows researchers to perturb brain function, measure the resulting changes in brain dynamics and relate those to changes in contamination anxiety or other behavioral measures. In addition, the establishment of this method serves as a first step towards the investigation of fMRI-based biofeedback as a therapeutic intervention for OCD. Given that approximately a quarter of patients with OCD receive little benefit from the currently available forms of treatment, and that those who do benefit rarely recover completely, new approaches for treating this population are urgently needed.

The case for including Attenuated Psychotic Symptoms Syndrome in DSM-5 as a psychosis risk syndrome.

The American Psychiatric Association Task Force on DSM-5 has recently proposed consideration of Attenuated Psychotic Symptoms Syndrome as a new diagnosis, based on nearly 15 years of prospective research in centers across the globe. The condition is also known as "psychosis risk syndrome," "at-risk mental state," "ultra-high risk," and "putative prodrome." We review evidence favoring its inclusion as a new diagnosis in DSM-5 and report new preliminary findings on DSM-IV diagnoses in current clinical use for these patients and on results of diagnostic interviews in unselected volunteers. The main evidence supporting inclusion is: (1) the patients are currently ill, (2) the patients are at high risk for getting worse, (3) no DSM-IV diagnosis accurately captures their current illness or future risk, (4) the diagnosis has been made with reliability and validity in the research setting, and (5) placement in DSM-5 would help promote the needed treatment and prevention research to enable articulation of a standard of care to benefit these patients and their families. Potential harms can be minimized by patient, family, and provider education. It will be important to demonstrate through well-designed field trials whether the diagnostic criteria can be used with reliability in everyday clinical practice.

High dose D-serine in the treatment of schizophrenia.

BACKGROUND: D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day). METHODS: 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses> or =30 mg/kg was also evaluated. RESULTS: Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses> or =60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. DISCUSSION: These findings support double-blind investigation of D-serine at doses> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

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.

Cognitive behavior therapy for early psychosis: a comprehensive review of individual vs. group treatment studies.

Several recent studies of individually administered cognitive behavior therapy (CBT) for early psychosis have reported only modest treatment benefits. The purpose of the current study was to review the literature to determine how outcomes of group CBT differ from outcomes of individually administered CBT among early cases. Our findings suggest that group CBT for early psychosis may be a more effective modality for this group of patients. We speculate that patients' uncertainty about illness in general may impair the effectiveness of individually administered CBT for early cases and that group CBT may be more effective for these young patients by better addressing those factors with the aid of peer-to-peer interactions, identification, and modeling.

Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of levetiracetam versus placebo for tardive dyskinesia (TD). METHOD: This double-blind, placebo-controlled, randomized study was conducted at the Connecticut Mental Health Center between September 2004 and April 2006. Antipsychotic-treated patients meeting Glazer-Morgenstern criteria for TD were assigned at random to receive levetiracetam 500 mg/day to 3000 mg/day or placebo for 12 weeks. After completion of 12 weeks, patients were permitted to receive open-label levetiracetam for a further 12 weeks. The principal efficacy outcome measure was improvement in the Abnormal Involuntary Movement Scale (AIMS) total score. Safety was assessed with an adverse event scale, psychiatric symptom rating scales, weight, and hematologic tests. RESULTS: A total of 50 patients were randomly assigned to treatment. AIMS total scores were moderate in severity at baseline. Mixed regression models revealed that AIMS total scores declined 43.5% from baseline in the levetiracetam group compared to 18.7% for placebo (p = .022). Patients continuing levetiracetam in the open-label phase continued to improve, and patients crossed over to open-label levetiracetam improved to a similar degree as those initially assigned. Levetiracetam was well tolerated. CONCLUSION: Levetiracetam appeared effective for TD in this study. The mechanisms of its therapeutic effect are unclear but may involve reducing neuronal hypersynchrony in basal ganglia. Future studies should attempt to replicate the current results. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00291213.

Predictors and time course of response among panic disorder patients treated with cognitive-behavioral therapy.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is well documented as an efficacious treatment for panic disorder. We provided open CBT treatment to patients who subsequently participated in a maintenance treatment study. This article reports on predictors and trajectory of response in 381 participants who completed treatment at 4 sites. METHOD: Participants who met criteria for panic disorder with or without agoraphobia (N = 381) completed assessment and entered treatment. Of these, 256 completed 11 sessions of CBT delivered by trained and supervised research therapists. Raters trained to reliability obtained demographic data and administered structured diagnostic interviews and the Hamilton Rating Scales for Depression and Anxiety and the Panic Disorder Severity Scale (PDSS) measures at baseline and posttreatment. We obtained self-report (SR) measures of anxiety sensitivity and adult separation anxiety at baseline and posttreatment and PDSS-SR ratings weekly. The study was conducted between November 1999 and July 2002. RESULTS: Treatment response rate was 65.6% for completers and 44.1% for the intent-to-treat sample. Greater severity of panic disorder and lower levels of adult separation anxiety predicted response. Beginning at week 4, responders showed greater mean decreases in PDSS scores than non-responders and maintained the advantage throughout the treatment. By week 6, 76% of responders, compared to 36% of nonresponders, recorded PDSS scores at least 40% below baseline on 2 consecutive weeks (odds ratio = 5.42, 95% CI = 3.10 to 9.48). CONCLUSION: These results suggest that CBT is just as effective for more severe panic disorder patients as it is for those with less severe panic disorder, regardless of other comorbid disorders, including agoraphobia. However, patients experiencing adult separation anxiety disorder are less likely to respond. Our results further inform clinicians that many people who will respond to 11 weeks of treatment will have done so by the middle of the treatment.

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.

Mood-stabilizer-maintained, remitted bipolar patients: taper and discontinuation of adjunctive antipsychotic medication.

The aim of this study was to determine whether bipolar patients who had been stabilized on combined antipsychotic and mood-stabilizer medications and were currently in remission benefited from continuation of the antipsychotic medication. Remitted bipolar patients were randomly assigned to either remain on adjunctive antipsychotic medication or to taper to placebo. Antipsychotic/placebo medication assignment was double-blind. Subjects were outpatients at a university-affiliated community mental health center. Fifteen subjects consented and proceeded with eligibility assessments. Five subjects were never randomized. One of these was excluded when the Structured Clinical Interview for DSM-IV interview revealed schizoaffective disorder. The remaining four subjects were not randomized for other reasons. Three randomized subjects never received study medications, or were withdrawn by the investigator within 1 week after beginning study medications. The seven remaining subjects received study medication for more than 1 week. Five subjects were randomized to taper to placebo and two to antipsychotic continuation. Of the five randomized to taper to placebo, three successfully tapered and completed the year of follow-up in continuous remission. One subject became manic 4 months after taper was completed, and one subject became psychotic, in the absence of a mood episode, during taper. Of the two subjects randomized to double-blind antipsychotic continuation, both completed the year of follow-up in continuous remission. When adjunctive antipsychotic medications are discontinued, bipolar patients' clinical symptoms can remain unchanged. Others are, however, at risk for manic relapse.