Cross-correlation registration algorithm enhancements for multipixel inverse synthetic aperture LiDAR.

The accurate registration and realignment of complex signal volumes is critical for cross-range aperture gain in 3D LiDAR aperture synthesis. For targets at long range, only a limited number of diffraction-limited pixels will be projected on the target, resulting in low cross-range support. In addition, the signal-to-noise ratio (SNR) is typically low. This research describes an enhanced cross-correlation registration algorithm for 3D inverse synthetic aperture LiDAR data volumes that improves performance for low cross-range support, low SNRs, and relatively large aperture shifts. The registration performance is improved through statistical removal of the cross-correlation noise pedestal and compensation for the reduced signal overlap caused by larger shifts. The registration performance is characterized as a function of SNR, signal shift (target rotation rate), and target pixel support. The algorithm's improvements allow for registration convergence at 1-5 dB lower SNR than the baseline cross-correlation algorithm. In addition, the algorithm enhancements allow for registration convergence at 10%-20% greater shifts.

Enhanced norepinephrine output during long-term desipramine treatment: a possible role for the extraneuronal monoamine transporter (SLC22A3).

To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.

Sequencing of substance use and affective morbidity in 166 first-episode bipolar I disorder patients.

OBJECTIVES: Since bipolar disorder (BPD) patients have high rates of comorbid substance abuse, and the temporal relationships involved are unclear, we evaluated the sequencing of specific substance use and affective morbidity. METHODS: Prospective follow-up (4.7 years) of 166 first-episode DSM-IV type I BPD patients with reliable, standardized assessments provided data for longitudinal analysis of temporal distribution of alcohol and cannabis use versus manic or depressive episodes or symptoms, using generalized estimating equation regression modeling. RESULTS: By quarters, cannabis use selectively and strongly preceded and coincided with mania/hypomania, and alcohol use preceded or coincided with depression, whereas substance use was unassociated with mood states in preceding quarters. CONCLUSIONS: These preliminary findings suggest potentially predictive temporal associations, in which the abuse of cannabis or alcohol anticipated or corresponded with, but did not follow, affective morbidity, including selective association of cannabis with mania and alcohol with depression.

Suicidal events and accidents in 216 first-episode bipolar I disorder patients: predictive factors.

BACKGROUND: Risks of life-threatening behaviors are high among bipolar disorder (BPD) patients, but early rates and associated risk factors for suicides and accidents remain ill-defined. METHODS: We assessed 216 DSM-IV BP-I patients prospectively for 4.2 years from first-lifetime hospitalization, using ordinal logistic-regression to estimate risks and associated demographic and clinical factors among risk-groups with: [1] no suicidal ideation, acts, or accidents, [2] suicidal ideation only, [3] suicides and attempts, [4] accidents, and [5] both suicidal acts and accidents. RESULTS: Suicidal thoughts or acts were identified in 127/216 subjects/4.2 years (14%/year), including suicidal ideation in 88 (9.7%/year), and acts in 39 (4.3%/year: 38 attempts [17.6%/year], 1 suicide [0.11%/year]); 87% of acts occurred within a year of a first-episode. Life-threatening accidents occurred in 20 cases (2.2%/year) with a mean latency of 3.8 years, including 12 with suicidal ideation or attempts (60% co-occurrence of accidents and suicidality); alcohol was implicated in 25% of accidents. The 53 cases of violent behaviors (5.84%/year) included a fatal car-wreck and a suicide, for a mortality risk of 0.22%/year (2/216/4.2 years). Suicidality was associated with initial mixed-state, proportion of follow-up weeks in mixed-states or depression, and prior suicide attempts; accidents were associated selectively with initial mania or psychosis, later mania or hypomania, and alcohol abuse. Violent acts also were associated with use of more psychotropic medicines/person, and with use of antipsychotics or sedative-anxiolytics. LIMITATIONS: Treatment was clinical and uncontrolled, illness relatively severe, and statistical power limited. CONCLUSIONS: Early in BP-I disorder, risks of suicidal acts and accidents were high, inter-related, and associated with particular types of initial and later morbidity, suggesting some predictability and potential for preventive intervention.

Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry.

The effects of type 1 diabetes and key metabolic variables on brain structure are not well understood. Sensitive methods of assessing brain structure, such as voxel-based morphometry (VBM), have not previously been used to investigate central nervous system changes in a diabetic population. Using VBM, we compared type 1 diabetic patients aged 25-40 years with disease duration of 15-25 years and minimal diabetes complications with an age-matched, nondiabetic control group. We investigated whether lower than expected gray matter densities were present, and if so, whether they were associated with glycemic control and history of severe hypoglycemic events. In comparison with control subjects, diabetic patients showed lower density of gray matter in several brain regions. Moreover, in the patient group, higher HbA(1c) levels and severe hypoglycemic events were associated with lower density of gray matter in brain regions responsible for language processing and memory. Our study represents the first comprehensive study of gray matter density changes in type 1 diabetes and suggests that persistent hyperglycemia and acute severe hypoglycemia have an impact on brain structure.

A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence.

OBJECTIVE: Although bipolar disorder and substance use disorder frequently co-occur, there is little information on the effectiveness of behavioral treatment for this population. Integrated group therapy, which addresses the two disorders simultaneously, was compared with group drug counseling, which focuses on substance use. The authors hypothesized that patients receiving integrated group therapy would have fewer days of substance use and fewer weeks ill with bipolar disorder. METHOD: A randomized controlled trial compared 20 weeks of integrated group therapy or group drug counseling with 3 months of posttreatment follow-up. Sixty-two patients with bipolar disorder and current substance dependence, treated with mood stabilizers for >or=2 weeks, were randomly assigned to integrated group therapy (N=31) or group drug counseling (N=31). The primary outcome measure was the number of days of substance use. The primary mood outcome was the number of weeks ill with a mood episode. RESULTS: Intention-to-treat analysis revealed significantly fewer days of substance use for integrated group therapy patients during treatment and follow-up. Groups were similar in the number of weeks ill with bipolar disorder during treatment and follow-up, although integrated group therapy patients had more depressive and manic symptoms. CONCLUSIONS: Integrated group therapy, a new treatment developed specifically for patients with bipolar disorder and substance dependence, appears to be a promising approach to reduce substance use in this population.

A strategy for identifying phenotypic subtypes: concordance of symptom dimensions between sibling pairs who met screening criteria for a genetic linkage study of childhood-onset bipolar disorder using the Child Bipolar Questionnaire.

BACKGROUND: Specific symptom dimensions have been used to establish phenotypic subgroups in recent genetic studies of bipolar disorder. In preparation for a genetic linkage study of childhood-onset bipolar disorder (COBPD), we conducted an exploratory analysis of the concordance of prominent symptom dimensions between sibling pairs (N=260) who screened positive for COBPD. This report presents data on the potential usefulness of these dimensions in genotyping. METHOD: A principal components factor analysis was conducted on the symptoms of 2795 children who screened positive for COBPD on the Child Bipolar Questionnaire (CBQ). The resulting factors were used in a concordance analysis between 260 proband/sibling pairs and 260 proband/matched comparison pairs. RESULTS: Ten factors were extracted. The strongest concordance coefficients (rho) between probands and siblings, and the widest contrasts between proband/sibling vs. proband/comparison pairs, were for Factor 9 (Fear of harm), Factor 5 (Aggression), Factor 10 (Anxiety), Factor 4 (Sensory sensitivity), Factor 6 (Sleep-wake cycle disturbances), and Factor 2 (Attention/Executive function deficits). Based on factor loadings and multivariate analyses, CBQ items were selected for a "Core Index" subscale that had a robust concordance estimate in the sibpair group (rho=0.514, 95% CI 0.450-0.577) as compared to the proband-matched comparison group (rho=0.093, 95% CI 0.008 to 0.178). LIMITATIONS: Research diagnostic interviews (K-SADS P/L) were conducted to confirm bipolar diagnosis in only a subsample (N=100) of the children whose data were used for the concordance analysis. CONCLUSIONS: Our data suggest a profile of heritable clinical dimensions in addition to classic mood symptomatology in COBPD. These features may represent a more homogeneous phenotypic subtype of COBPD that may prove more useful for delineating the neurobiology and genetics of the disorder than standard diagnostic models.

Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders.

OBJECTIVE: Bipolar disorders are prevalent major illnesses with high rates of morbidity, comorbidity, disability, and mortality. A growing number of psychotropic drugs are used to treat bipolar disorder, often off-label and in untested, complex combinations. METHODS: To quantify utilization rates for psychotropic drug classes, this study used the 2002-2003 U.S. national MarketScan research databases to identify 7,760 persons with ICD-9 bipolar disorder subtypes. Survival analysis was used to estimate times until initial monotherapies were augmented, changed, or discontinued. RESULTS: The most commonly prescribed first drug class was antidepressants (50% of patients), followed by mood stabilizers (25%: anticonvulsants, 17%, and lithium, 8%), sedatives (15%), and antipsychotics (11%). At study midpoint only 44% of patients were receiving monotherapy. Those receiving monotherapy were ranked by initial drug prescribed and percentage of patients (bipolar I and bipolar II): antidepressants (55% and 65%), lithium (51% and 41%), antipsychotics (32% and 31%), anticonvulsants (28% and 29%), and sedatives (28%, 25%). Median time to adding another psychotropic was 2.5-times less than median time to changing the initial treatment (16.4 compared with 40.9 weeks), and stopping was rare. Median weeks until therapy was changed in any way for 25% of patients was as follows: lithium, 29 weeks; antidepressants, 13; anticonvulsants, 13; antipsychotics, 13; and sedatives, 9. CONCLUSIONS: Antidepressants were the first-choice agent twice as often as mood stabilizers. Lithium was sustained longer than monotherapy with other mood stabilizers. Time to augmentation was much shorter than time to change or discontinuation.

Prediction of the 10-year course of borderline personality disorder.

OBJECTIVE: The purpose of this study was to determine the most clinically relevant baseline predictors of time to remission for patients with borderline personality disorder. METHOD: A total of 290 inpatients meeting criteria for both the Revised Diagnostic Interview for Borderlines and DSM-III-R for borderline personality disorder were assessed during their index admission with a series of semistructured interviews and self-report measures. Diagnostic status was reassessed at five contiguous 2-year time periods. Discrete survival analytic methods, which controlled for baseline severity of borderline psychopathology and time, were used to estimate hazard ratios. RESULTS: Eighty-eight percent of the patients with borderline personality disorder studied achieved remission. In terms of time to remission, 39.3% of the 242 patients who experienced a remission of their disorder first remitted by their 2-year follow-up, an additional 22.3% first remitted by their 4-year follow-up, an additional 21.9% by their 6-year follow-up, an additional 12.8% by their 8-year follow-up, and another 3.7% by their 10-year follow-up. Sixteen variables were found to be significant bivariate predictors of earlier time to remission. Seven of these remained significant in multivariate analyses: younger age, absence of childhood sexual abuse, no family history of substance use disorder, good vocational record, absence of an anxious cluster personality disorder, low neuroticism, and high agreeableness. CONCLUSIONS: The results of this study suggest that prediction of time to remission from borderline personality disorder is multifactorial in nature, involving factors that are routinely assessed in clinical practice and factors, particularly aspects of temperament, that are not.

The child bipolar questionnaire: a dimensional approach to screening for pediatric bipolar disorder.

BACKGROUND: The Child Bipolar Questionnaire (CBQ) is a rapid screener with a Core Index subscale of symptom dimensions frequently reported in childhood-onset bipolar disorder (BD) and scoring algorithms for DSM-IV BD, with and without attention-deficit/hyperactivity disorder (ADHD), and the proposed Narrow, Broad, and Core phenotypes. This report provides preliminary data on the reliability and validity of the CBQ. METHOD: Test-retest and inter-rater reliability of the CBQ were assessed. The ability of CBQ screening diagnoses and of the CBQ Core Index subscale to effectively predict diagnostic classification by structured interview was assessed using the K-SADS P/L. RESULTS: Preliminary test-retest data showed excellent reliability for both the CBQ total score (r = 0.82) and the Core Index subscale (r = 0.86). Preliminary validity data was also promising. CBQ screening algorithms performed with a specificity of 97% and a sensitivity of 76% in classifying subjects with K-SADS P/L diagnosis of BD vs. no BD. The Core Index subscale had excellent agreement with K-SADS P/L diagnosis (k = 0.84) in classifying BD, ADHD-only, and no diagnosis and demonstrated 100% sensitivity and 86% specificity in classifying BD vs. no BD. LIMITATIONS: This preliminary data is from a sample enriched with bipolar disorder cases. Further validation is needed with samples in which childhood-onset BD is rarer and diagnoses more diverse. CONCLUSIONS: The CBQ shows potential for rapid and economically feasible identification of possible childhood-onset BD cases as defined by DSM-IV criteria as well as by alternate disease phenotypes. Further validation studies will focus on inpatient and outpatient samples with a broader range of variability.

Manual assisted cognitive treatment for deliberate self-harm in borderline personality disorder patients.

This study examines the efficacy of a short-term individual therapy, Manual Assisted Cognitive Treatment (MACT), which was developed to treat parasuicidal (suicidal or self-harming) patients. In this trial, MACT was modified to focus on deliberate self-harm (DSH) in patients with borderline personality disorder (BPD). Thirty BPD patients who were engaged in DSH while in ongoing treatments, i.e., treatment-as-usual (TAU), were randomly assigned to receive MACT (N = 15) or not. DSH and level of suicide ideation were assessed at the baseline, at completion of the MACT intervention, and six months later. Results indicated that MACT was associated with significantly less frequent DSH upon completion of the intervention and with significantly decreased DSH frequency and severity at the six months follow-up. Moreover, MACT's contribution to reducing DSH frequency and severity was greater than the contribution by the amount of concurrent treatments. In contrast, MACT did not affect the level of suicide ideation and time-to-repeat of DSH. In conclusion, MACT seems to be a promising intervention for DSH in patients with BPD. More definitive studies are needed.

Reported childhood onset of self-mutilation among borderline patients.

The purpose of this study was to determine the percentage of borderline patients who first engaged in self-mutilation as children and to compare the parameters of their self-harm to those of borderline patients who first harmed themselves at an older age. Two hundred and ninety inpatients meeting both Revised Diagnostic Interview for Borderlines (DIB-R; Zanarini, Gunderson, Frankenburg, & Chauncey, 1989) and Diagnostic and Statistical Manual of Mental Disorders (3rd ed. ref.) (DSM-III-R; APA, 1987) criteria for borderline personality disorder were interviewed about their history of self-mutilation. Of the 91% with a history of self mutilation, 32.8% reported first harming themselves as children (12 years of age or younger), 30.2% as adolescents (13-17 years of age), and 37% as adults (18 or older). Using logistic regression analyses and controlling for baseline age, it was found that those with a childhood onset reported more episodes of self-harm, a longer duration of self-harm, and a greater number of methods of self-harm than either those with an adolescent or adult onset to their self-mutilation. The results of this study suggest that a sizable minority of borderline patients first engage in self-harm as children and that the course of their self-mutilation may be particularly malignant.

An ongoing study of group treatment for men involved in problematic Internet-enabled sexual behavior.

Exponential advances have been made regarding computer/Internet technology in the past decade. This growth, in large part, can be attributed to greater access to, affordability of, and anonymity while on the computer. However, this progress has also produced negative psychological issues. Problematic Internet-enabled sexual behavior (IESB) has increasingly affected individuals' family relationships, work productivity, and academic success. This article is the first-known, empirically based outcome study regarding the effectiveness of group therapy treatment for men with problematic IESB. These closed-groups, which ran for 16 weeks, used a combination of Readiness to Change (RtC), Cognitive Behavioral Therapy (CBT), and Motivational Interviewing (MI) interventions. Five groups were analyzed for this paper (yielding a total N of 35), with the average member's age being 44.5 years old. Three different scales (the Orzack Time Intensity Survey, the BASIS-32, and the BDI) were used to track participants' progress across time. The results demonstrated that this group treatment intervention significantly increased members' quality of life and decreased the severity of their depressive symptoms. However, the protocol failed to reduce participants' inappropriate computer use. Regarding comorbidity, the results showed the following: members in the "anxiety" category responded best to the current treatment, those in the "mood" cluster responded relatively positively, and those in the "A-D/HD" category failed to respond significantly. It is clear from this report that more attention must be focused on the treatment of problematic IESB, as opposed to exploratory studies.

Double-blind, placebo-controlled, multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in outpatients with schizophrenia.

OBJECTIVE: The authors' goal was to test the efficacy of selegiline augmentation of antipsychotic medication in outpatients with schizophrenia who had negative symptoms of moderate or greater severity. METHOD: A 12-week, double-blind, placebo-controlled, multicenter trial of oral selegiline augmentation of antipsychotic medication was carried out. Outpatients were chosen who did not manifest severe positive symptoms at baseline, who did not meet criteria for coexisting major depression, and who had been maintained on a stable regimen of antipsychotic medication. RESULTS: Negative symptoms were found to be significantly more improved in the patients who received selegiline, and global improvement scores reinforced the impression that selegiline augmentation was beneficial. CONCLUSIONS: These findings support further investigation of low-dose selegiline augmentation of antipsychotic medication in outpatients with schizophrenia who have at least a moderate burden of negative symptoms.

Substance abuse in first-episode bipolar I disorder: indications for early intervention.

OBJECTIVE: This study clarified the early characteristics of substance use disorders in patients with first-episode bipolar I disorder. METHOD: The authors evaluated substance use disorders, associated factors, and clinical course, prospectively, in the first 2 years of DSM-IV bipolar I disorder with standardized methods. RESULTS: Baseline substance use disorder was found in 33% (37 of 112) of the patients at baseline and in 39% at 24 months. Anxiety disorders were more frequent in the patients with than without substance use disorder (30% and 13%, respectively). Associations of alcohol dependence with depressive symptoms and cannabis dependence with manic symptoms were suggested. Patients using two or more substances had worse outcomes. CONCLUSIONS: Since substance use disorders were frequent from the beginning of bipolar I disorder and were associated with anxiety disorders and poor outcome, early interventions for substance use disorder and anxiety might improve later outcome.

A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: A 19-F MRS study.

Racemic fluoxetine consists of R- and S-fluoxetine, which are metabolized to R- and S-norfluoxetine, respectively. This study was designed to compare brain levels achieved with R-fluoxetine to those achieved with racemic fluoxetine in healthy subjects using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS). In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 microM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable. While these data support the use of MRS to aid in defining the therapeutic dose range for drug development, they also highlight the need for additional studies with concurrent animal models to establish the validity of using serum drug/metabolite ratios to interpret MRS determined brain drug levels.

Assessing the utility of atypical antipsychotic medication in adults with mild mental retardation and comorbid psychiatric disorders.

OBJECTIVE: Research on psychiatric outcomes among individuals dually diagnosed with mild mental retardation and co-occurring mental illness who are treated with antipsychotic medication is markedly limited due to difficulties encountered in (1) making valid and reliable psychiatric diagnoses and (2) accurately rating and following psychiatric symptom change over time in this specialty population. METHOD: To address these issues, DSM-IV psychiatric diagnoses were made by an experienced dual-diagnosis clinician, and the Aberrant Behavior Checklist (ABC) and the Global Assessment of Functioning were used to assess behavioral and psychiatric features in a psychiatric partial hospital setting. Data were collected by chart review from 72 patients admitted consecutively from January 1998 to December 1999. Assessments were compared at admission and discharge in this retrospective study for 3 treatment groups that were defined by antipsychotic medication status at discharge: no antipsychotic (N = 15), atypical antipsychotic only (N = 41), and mixed atypical/typical antipsychotics or typical anti-psychotic only (N = 16). RESULTS: Improvement on the ABC social withdrawal subscale was greater for atypical anti-psychotic medication-treated, dually diagnosed patients than for those who received other treatment regimens. In addition, a dose-response relationship was observed for this subscale and atypical antipsychotic medication dose. CONCLUSION: For certain psychotic patients with mild mental retardation, the atypical antipsychotics may be an appropriate and effective treatment modality.

Long-term combination therapy versus monotherapy with lithium and carbamazepine in 46 bipolar I patients.

BACKGROUND: Despite wide clinical use of mood-stabilizer combinations for long-term treatment of patients with bipolar disorder, research on risks and benefits of this practice is limited. We found 14 small, usually brief, clinical trials of maintenance treatment with lithium plus carbamazepine. These trials suggest added benefit of combination treatment over use of either agent alone but also indicate the need for further studies. METHOD: In a post hoc analysis, we reviewed the course of 46 patients with DSM-IV-diagnosed bipolar I disorder identified as not improving during long-term monotherapy in a mood disorders clinic, comparing days per year hospitalized in 3 consecutive time periods: before prophylactic treatment, during monotherapy with lithium (N = 31) or carbamazepine (N = 15), and during their combined use (N = 46). Secondary outcome measures were rates of hospitalization, time to first recurrence of an affective episode, use of adjunctive treatments, and adverse effects. We compared outcomes with nonparametric bivariate methods and tested predictive factors by multiple regression. RESULTS: Subjects showed significant reductions in hospitalized days per year during combination therapy, averaging a decrease of 55.9% (p = .004). Among secondary outcomes, hospitalizations per year fell by 36.1%, and median time to recurrence nearly doubled during combination therapy. Rates of adverse effects increased 2.5-fold, compared with monotherapy, and use of adjunctive psychotropic agents increased by 21.9%. CONCLUSION: Combining lithium with carbamazepine yielded substantial benefit but more adverse effects.

Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment.

RATIONALE: There is evidence that prefrontal lobe GABA levels are low in cocaine-dependent (CD) individuals, and treatment with GABA agonists decreases cocaine self-administration. OBJECTIVES: The aim of the study is to measure changes in GABA levels in CD subjects at baseline and after 8 weeks of treatment with pramipexole, venlafaxine, or placebo. METHODS: CD subjects enrolled in a treatment trial for cocaine dependence were recruited for this proton (1H) magnetic resonance spectroscopy (MRS) study. GABA levels in the prefrontal lobe were measured before and after treatment. RESULTS: Mean percentage changes in GABA levels were as follows: pramipexole +17.0+/-28.0%, venlafaxine +13.0+/-11.0%, and placebo -2.1+/-19.5%. Pramipexole-treated subjects had significantly increased brain GABA levels compared to placebo (p=0.031). Venlafaxine treatment was nonsignificantly associated with increased GABA levels compared to placebo (p=0.16). The overall statistical model for the effect of drug treatment vs placebo on brain GABA levels, including adjustment for baseline levels, was highly significant (p=0.002). Despite significant changes in GABA levels, there were no significant differences in the number of urine samples positive for cocaine metabolites. CONCLUSIONS: This study demonstrates that 1H MRS can measure changes in GABA levels following pharmacologic treatment. The increase in GABA levels, although significant, is modest compared to other MRS studies of depression or epilepsy associated with clinical improvements. The failure to see larger increases in GABA levels and an associated reduction in cocaine consumption may reflect the relatively low doses of medication used.

Suicidal risk during treatment with clozapine: a meta-analysis.

OBJECTIVE: Suicide remains a major cause of premature mortality among patients with schizophrenia. Evidence of reduced suicidal risk with available psychiatric treatments is limited, but emerging data suggest such an effect of clozapine in chronically psychotic patients, leading us to compile the reported evidence. METHOD: We searched for published studies with contrasting rates of suicides or attempts by psychotic patients treated with clozapine vs. other agents. RESULTS: Among six such studies, random-effects meta-analysis indicated a substantially lower overall risk of suicidal behaviors with clozapine vs. other treatments (risk-ratio 3.3; 95% confidence interval [CI] 1.7-6.3; p<0.0001). For completed suicides, the risk ratio (RR) was 2.9 ([CI 1.5-5.7]; p=0.002). CONCLUSION: Long-term treatment with clozapine was associated with three-fold overall reduction of risk of suicidal behaviors. However, available findings are quantitatively inconsistent, well-designed studies remain rare, and the only randomized trial did not find reduced risk of completed suicide. Additional randomized comparisons among modern treatments for psychotic disorders are required to clarify their impact on mortality.