Feasibility and Effect of Increasing Clozapine Plasma Levels in Long-Stay Patients With Treatment-Resistant Schizophrenia.

BACKGROUND: It is unknown whether increasing the clozapine plasma level to 400, 750, or even 1000 ng/mL is a feasible and effective strategy in patients with treatment-resistant schizophrenia (TRS). We investigated this in long-stay patients with TRS. METHODS: In long-stay TRS patients, doses of clozapine were increased gradually to reach target plasma levels of 400, 750, or 1000 ng/mL, depending on the clinical response and tolerability. After an effective or tolerated level was reached, positive and negative syndrome scale scores were evaluated after 3 months and 1 year. RESULTS: Twenty-eight patients were included. Overall, 54% of the patients, and especially patients 60 years and older, could not achieve one of the clozapine target levels because of adverse effects. Three physically vulnerable patients died, probably not directly related to clozapine use. Although only 21% of patients achieved a more than 20% reduction in total symptoms at the 1-year follow-up, the mean severity of positive symptoms decreased from 18.18 to 15.10 ( P < 0.01). The largest decrease in positive symptoms was seen in TRS patients who achieved a plasma level of 750 ng/mL of clozapine. CONCLUSIONS: Most TRS patients older than 60 years could not tolerate high clozapine levels and so this should not be attempted in older or otherwise physically vulnerable patients. Increasing clozapine levels to approximately 750 ng/mL in middle-aged patients with longstanding TRS may modestly reduce the severity of positive symptoms and improve the response rate.

Symptom networks in patients with substance use disorders.

BACKGROUND: Reciprocity between symptoms of psychiatric disorders is increasingly recognized to contribute to their chronicity. In substance use disorders (SUD) little is known on reciprocal interactions between symptoms. We applied network analyses to study these interactions. METHODS: We analyzed 11 DSM-IV / DSM-5 criteria for SUD for the most prevalent substances in addiction care (alcohol, cannabis, cocaine, stimulants, and opioids) in a sample of 10,832 SUD patients in treatment. First, we estimated an overall symptom network. Second, we compared symptom networks between the different substances. Finally, we tested differences in symptom networks between DSM-IV and DSM-5. RESULTS: In the overall symptom network for SUD patients the most central symptom was: "spending substantial amount of the day obtaining, using, or recovering from substance use". The symptoms "giving up or cutting back on important activities because of use" and "repeated usage causes or contributes to an inability to meet important obligations", were the symptoms that influenced each other the most. Networks differed between substances both in global strength and structure, especially regarding the position of "use despite health or interpersonal problems". Networks based on DSM-5 criteria differed moderately from DSM-IV, mainly because "craving" was more central in the DSM-5 network than "legal problems" in DSM-IV. CONCLUSIONS: Network analyses can identify core symptoms of SUD that could maintain the disease processes in SUD. Future studies should address whether targeting these core symptoms with precedence, might help to break through the addictive process.

Appraisal-based cognitive bias modification in patients with posttraumatic stress disorder: a randomised clinical trial.

Background: Negative appraisals of the trauma and its sequelae play a crucial role in the development and maintenance of Posttraumatic Stress Disorder (PTSD). Experimental studies have shown promise in reducing negative appraisal through Cognitive Bias Modification (CBM) training. Objective: To determine whether an online CBM training designed to modify dysfunctional appraisals is successful in reducing appraisal bias in PTSD patients. Method: In this double-blinded 2-arm randomised clinical trial, 107 patients with PTSD were randomly allocated to active (n = 49) or control online CBM training (n = 57). Training comprised the completion of four sessions of online CBM training within one week. Change in bias, as measured by a scenario task and questionnaire (i.e. PostTraumatic Cognition Inventory), was the primary outcome. Secondary outcome included change in PTSD symptoms. Assessments took place prior to training, during training sessions, post-training and at 1- and 6-month follow-up. Results: Intent-to-treat analysis indicated that there was no interaction effect of condition by time. Regardless of training condition, participants showed a small to moderate decline in appraisal bias and PTSD symptoms from pre- to post-training. In both conditions, bias change during training sessions was related to decline in PTSD symptomatology following training. No moderators of outcome were found. Conclusions: There was no evidence that active training was more effective than control training in reducing dysfunctional appraisals. In both conditions, participants showed a decline in dysfunctional appraisals and PTSD symptoms following training. Importantly, bias reduction during training was related to PTSD symptom decline following training. Explanations and future research directions are discussed.

Antecedentes: Las valoraciones negativas del trauma y sus secuelas juegan un rol crucial en el desarrollo y mantención del Trastorno de Estrés Postraumático (TEPT). Estudios experimentales han mostrado promesa en reducir las valoraciones negativas a través de un entrenamiento de modificación de sesgo cognitivo (MSC).Objetivo: Determinar si un entrenamiento MSC en línea diseñado para modificar valoraciones disfuncionales es exitoso en reducir sesgos de valoración en pacientes con TEPT.Método: En este ensayo clínico randomizado doble ciego de 2 ramas, 107 pacientes con TEPT fueron asignados a entrenamiento MSC en línea activo (n=49) o control (n=57). El entrenamiento incluyó la realización de cuatro sesiones de entrenamiento MSC en línea dentro de una semana. El cambio en el sesgo, medido por un escenario de tareas y cuestionario (por ej. Inventario de Cogniciones Postraumáticas), fue el resultado primario. El resultado secundario incluyó cambios en los síntomas de TEPT. Las evaluaciones fueron realizadas antes del entrenamiento, durante las sesiones de entrenamiento, y posterior al tratamiento al mes y a los 6 meses de seguimiento.Resultados: El análisis del tipo intención de tratar indicó que no hubo efecto en la interacción de la condición según el tiempo. Pese a la condición de entrenamiento, los participantes mostraron una disminución leve a moderada en el sesgo de valoración y síntomas de TEPT desde el periodo anterior y posterior al entrenamiento. En ambas condiciones el cambio en el sesgo durante las sesiones de entrenamiento se relacionó con la disminución de la sintomatología de TEPT tras el entrenamiento. No se encontraron moderadores de resultados.Conclusiones: No hubo evidencia de que el entrenamiento activo fuera más efectivo que el entrenamiento control en reducir las valoraciones disfuncionales. En ambas condiciones, los participantes mostraron una disminución en las valoraciones disfuncionales y síntomas de TEPT tras el entrenamiento. De forma importante, la reducción del sesgo se relacionó con la disminución de sintomatología de TEPT tras el entrenamiento. Explicaciones y orientaciones sobre futura investigación fueron discutidas.

Dose reduction of high-dose first-generation antipsychotics or switch to ziprasidone in long-stay patients with schizophrenia: A 1-year double-blind randomized clinical trial.

Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms and side effects. We investigated in a randomized double-blind trial whether a dose-reduction strategy to achieve an adequate dose of a FGA (5 mg/day haloperidol equivalents, n = 24) or switching to ziprasidone (160 mg/day, n = 24) in treatment resistant patients would decrease negative symptoms after 1 year of treatment. We found that negative symptoms did not change significantly in either condition. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference between conditions in favour of FGA dose reduction. Relapse and treatment failure, defined as a prolonged or repeated relapse, occurred more often with ziprasidone than with FGA (45.8% versus 20.8%, and 25.0% versus 16.7%, respectively). Treatment with ziprasidone was superior for extrapyramidal symptoms. Our study establishes that lowering high FGA doses to an equivalent of 5 mg/day haloperidol or switching to ziprasidone is feasible in the vast majority of patients but does not improve negative or other symptoms. Neither FGA dose reduction nor switching to ziprasidone is an adequate alternative to clozapine for long-stay patients with severe treatment resistant schizophrenia.

Intensive prolonged exposure therapy for chronic PTSD patients following multiple trauma and multiple treatment attempts.

Background: Suboptimal response and high dropout rates leave room for improvement of trauma-focused treatment (TFT) effectiveness in ameliorating posttraumatic stress disorder (PTSD) symptoms. Objective: To explore the effectiveness and safety of intensive prolonged exposure (iPE) targeting chronic PTSD patients with a likely diagnosis of ICD-11 Complex PTSD following multiple interpersonal trauma and a history of multiple treatment attempts. Method: Participants (N = 73) received iPE in 12 × 90-minute sessions over four days (intensive phase) followed by four weekly 90-minute booster prolonged exposure (PE) sessions (booster phase). The primary outcomes, clinician-rated severity of PTSD symptoms, and diagnostic status (Clinician-Administered PTSD Scale; CAPS-IV) were assessed at baseline, post-treatment, and at three and six months. Treatment response trajectories were identified and predictors of these trajectories explored. Results: Mixed model repeated measures analysis of CAPS-IV scores showed a baseline-to-posttreatment decrease in PTSD symptom severity (p < .001) that persisted during the three- and six-month follow-ups with large effect sizes (Cohen's d > 1.2); 71% of the participants responded. None of the participants dropped out during the intensive phase and only 5% during the booster phase. Adverse events were extremely low and only a minority showed symptom exacerbation. Cluster analysis demonstrated four treatment response trajectories: Fast responders (13%), Slow responders (26%), Partial responders (32%), and Non-responders (29%). Living condition and between-session fear habituation were found to predict outcome. Participants living alone were more likely to belong to the Partial responders than to the Non-responders cluster, and participants showing more between-session fear habituation were more likely to belong to the Fast responders than to the Non-responders cluster. Conclusions: The results of this open study suggest that iPE can be effective in PTSD patients with multiple interpersonal trauma and after multiple previous treatment attempts. In addition, in this chronic PTSD population iPE was safe.

Planteamiento: La respuesta subóptima y las altas tasas de abandono dejan margen para la mejora de la eficacia del tratamiento centrado en el trauma (TCT) en la mejora de los síntomas del trastorno por estrés postraumático (TEPT). Objetivo: explorar la efectividad y la seguridad de la exposición prolongada intensiva (EPI) dirigida a pacientes con TEPT crónico con un probable diagnóstico de TEPT complejo de la CIE-11 después de múltiples traumas interpersonales y un historial de múltiples intentos de tratamiento. Método: Los participantes (N = 73) recibieron EPI en 12 sesiones de 90 minutos durante cuatro días (fase intensiva) seguidas de cuatro sesiones semanales de exposición prolongada (EP) de refuerzo de 90 minutos (fase de refuerzo). Los resultados principales, la gravedad de los síntomas del TEPT evaluados por el clínico y el estado diagnóstico evaluados por el clínico (Escala de TEPT administrada por el clínico, CAPS-IV, por sus siglas en inglés) se evaluaron al inicio, después del tratamiento, y a los tres y seis meses. Se identificaron las trayectorias de respuesta al tratamiento y se exploraron los predictores de estas trayectorias. Resultados: Los análisis de medidas repetidas de las puntuaciones de CAPS-IV desde un modelo mixto mostraron una disminución de la línea de base hasta el postratamiento en cuanto a la gravedad de los síntomas de TEPT (p <.001) que persistió durante los seguimientos a los 3 y 6 meses con tamaños de efecto grandes (d de Cohen> 1,2); el 71% de los participantes respondieron. Ninguno de los participantes abandonó durante la fase intensiva y solo el 5% lo hizo durante la fase de refuerzo. Los eventos adversos fueron extremadamente bajos y solo una minoría mostró exacerbación de los síntomas. El análisis de clusters demostró cuatro trayectorias de respuesta al tratamiento: los que responden rápidamente (13%), los que responden lentamente (26%), los que responden parcialmente (32%) y los que no responden (29%). Se descubrió que las condiciones de vida y la habituación al miedo entre sesiones predecían el resultado. Los participantes que vivían solos eran más propensos a pertenecer a los que responden parcialmente que al grupo de los que no responden, y los participantes que demostraron más habituación al miedo entre sesiones tenían más probabilidades de pertenecer a los que responden rápidamente que al grupo de los que no responden. Conclusiones: los resultados de este estudio abierto sugieren que la EPI puede ser efectiva en pacientes con TEPT con traumas interpersonales múltiples y después de múltiples intentos previos de tratamiento. Además, en esta población de TEPT crónico, la EPI era segura.

Harm expectancy violation during exposure therapy for posttraumatic stress disorder.

Exposure therapy has proven efficacy in the treatment of posttraumatic stress disorder (PTSD). Emotional processing theory proposes that fear habituation is a central mechanism in symptom reduction, but the empirical evidence supporting this is mixed. Recently it has been proposed that violation of harm expectancies is a crucial mechanism of action in exposure therapy. But to date, changes in harm expectancies have not been examined during exposure therapy in PTSD. The goal of the current study was to examine harm expectancy violation as mechanism of change in exposure therapy for posttraumatic stress disorder (PTSD). Patients (N=50, 44 female) with a primary diagnosis of chronic PTSD received intensive exposure therapy. Harm expectancies, harm experiences and subjective units of distress (SUDs) were assessed at each imaginal exposure session, and PTSD symptoms were assessed pre- and posttreatment with the Clinician Administered PTSD Scale (CAPS). Results showed that harm expectancies were violated within and strongly declined in-between exposure therapy sessions. However, expectancy violation was not related to PTSD symptom change. Fear habituation measures were moderately related to PTSD symptom reductions. In line with theory, exposure therapy promotes expectancy violation in PTSD patients, but this is not related to exposure therapy outcome. More work is warranted to investigate mechanisms of change during exposure therapy in PTSD.

Low levels of vitamin D poorly responsive to daylight exposure in patients with therapy-resistant schizophrenia.

BACKGROUND: Low vitamin D levels are associated with schizophrenia, but the possible association between vitamin D levels and illness severity or duration of exposure to daylight has barely been investigated. AIMS: To compare vitamin D levels in therapy-refractory severely ill schizophrenia patients and members of staff. To investigate the influence of daylight exposure on vitamin D levels in patients. METHODS: Vitamin D was measured in patients with therapy-resistant schizophrenia in April, after the winter, and in patients and staff members in June, after an exceptionally sunny spring. Vitamin D levels in April and June were compared in patients, and levels in June were compared in patients and staff. The influence of daylight was taken into account by comparing the time patients spent outdoors during the day with the recommended minimum time for adequate vitamin D synthesis, and by comparing time spent outdoors in patients and staff. RESULTS: Patients had high rates of vitamin D deficiency (79-90%) and lower levels of vitamin D than staff members (p < 0.001), independent of skin pigmentation. In patients, vitamin D levels did not normalize, despite the considerably longer than recommended exposure of the skin to daylight (p < 0.001) and the longer exposure in patients than in staff members (p = 0.003). CONCLUSION: The vitamin D deficiency of therapy-resistant schizophrenia patients is pronounced and cannot be explained by differences in skin pigmentation or by an inactive, indoor lifestyle on the ward. Even theoretically sufficient exposure of the patients to daylight did not ameliorate the low vitamin D levels. CLINICAL IMPLICATIONS: While vitamin D deficiency probably plays a role in somatic health problems, it may also play a role in schizophrenia. Interestingly, exposure to daylight during an unusually sunny spring was not sufficient to correct the vitamin D deficiency seen in the patients. This emphasizes the need to measure and correct vitamin D levels in these patients.

Prescriptive variables for d-cycloserine augmentation of exposure therapy for posttraumatic stress disorder.

In recent years, several studies have demonstrated efficacy of d-cycloserine (DCS) enhanced exposure therapy across anxiety disorders. In this study we examined person-level variables that predicted response to DCS enhanced exposure therapy in a chronic, mixed trauma PTSD sample. The sample consisted of 67 treatment-seeking individuals, randomly allocated to receive exposure therapy augmented with DCS (50 mg) or identical looking placebo. We examined the following baseline predictors of treatment response: (1) demographic characteristics (age, gender, marital status, and education); (2) clinical characteristics (initial PTSD symptom severity, Axis I comorbidity, depression symptom severity, and antidepressants use); (3) personality characteristics (openness, conscientiousness, extraversion, agreeableness, and neuroticism). Outcome was measured with the PTSD Symptom Scale, Self-Report, which was assessed weekly during treatment. Two prescriptive variables were identified: conscientiousness and extraversion. For high conscientious participants, those who received DCS showed better outcome than those who received placebo. And for low extraversion, DCS showed superior outcome relative to placebo. Education was identified as a prognostic variable, it predicted response across both groups: higher education was related to worse outcome. Our results provide support for the influence of personality traits on DCS augmented exposure outcome and give more insight into possible working mechanisms of this novel treatment strategy. Ultimately, this may contribute to treatment matching strategies in order to improve treatment efficacy of exposure therapy for PTSD.

A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a complex and debilitating anxiety disorder, and, although prolonged exposure therapy has been proven effective, many patients remain symptomatic after treatment. In other anxiety disorders, the supplementary use of D-cycloserine (DCS), a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, showed promise in enhancing treatment effects. We examined whether augmentation of prolonged exposure therapy for PTSD with DCS enhances treatment efficacy. METHODS: In a randomized, double-blind, placebo-controlled trial we administered 50 mg DCS or placebo 1 hour before each exposure session to 67 mixed trauma patients, recruited from regular referrals, with a primary PTSD diagnosis satisfying DSM-IV criteria. RESULTS: Although DCS did not enhance overall treatment effects, the participants having received DCS did show a stronger treatment response. Exploratory session-by-session analyses revealed that DCS yielded higher symptom reduction in those participants that had more severe pretreatment PTSD and needed longer treatment. CONCLUSIONS: The present study found preliminary support for the augmentation of exposure therapy with DCS, specifically for patients with more severe PTSD needing longer treatment.

Measurements in the Addictions for Triage and Evaluation (MATE): an instrument based on the World Health Organization family of international classifications.

AIMS: To present and evaluate a measurement tool for assessing characteristics of people with drug and/or alcohol problems for triage and evaluation in treatment. Measurements in the Addictions for Triage and Evaluation (MATE) is composed of 10 modules, selected on the basis of a detailed set of specifications. Conceptually, the MATE was constructed according to the ICD and International Classification of Functioning (ICF) in the World Health Organization (WHO) classification system. Two of the ICF-related modules were newly designed. DESIGN: Monitoring feasibility and field-testing in a treatment-seeking population with researcher and clinician-administered test-retest interviews, construct validation with related instruments and evaluation of the dimensional structure of the ICF-related modules. SETTING: The research was conducted in a large, regional substance abuse treatment centre in the Netherlands and at the Municipal Health Service of Amsterdam. Participants A total of 945 treatment-seeking patients were recruited during routine intakes, 159 of whom were interviewed twice; 32 problem drug users were also recruited from the Amsterdam cohort studies among problem drug users. Findings Completion time was reasonably short, and there were relatively few missing data. The factor structure of the ICF-related modules revealed a three-factor model with an acceptable fit. Inter-rater reliability ranged between 0.75 and 0.92 and was satisfactory, but interviewer reliability ranged between 0.34 and 0.73, indicating that some of subscales need to be improved. Concurrent validity was indicated by significant correlations (>0.50) between the ICF-related modules and the WHO Disability Assessment Schedule II (WHODAS II) and WHO Quality of Life brief version (WHOQOL-BREF). CONCLUSIONS: The MATE can be used to allocate patients to substance abuse treatment. Because it is a comprehensive but flexible measurement tool that is also practical to use, the MATE is well suited for use in a heterogeneous population.

Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients.

BACKGROUND: Alternatives to lithium for prophylactic treatment of patients with bipolar affective disorders are increasingly being advocated. However, trials comparing lithium with alternatives are scarce and often biased. METHOD: We studied 94 patients with at least 2 episodes of bipolar disorder (DSM-III-R) during the previous 3 years who were in remission at entry into the study. Treatment with lithium or carbamazepine had not exceeded a total of 6 months during their lifetime. Patients were randomly assigned to carbamazepine or lithium at entry into the 2-year double-blind study or during the acute index episode previous to entry into the study. No concurrent antipsychotics or antidepressants were allowed. RESULTS: On lithium treatment, 12/44 patients developed an episode, compared with 21/50 on carbamazepine treatment. Episodes on lithium treatment occurred almost exclusively during the first 3 months of the trial. Carbamazepine carried a constant risk of an episode of about 40% per year. Efficacy of lithium was superior to that of carbamazepine in patients with a (hypo)manic index episode that had not been treated with study drug during the index episode (p <.01) and also in patients with prior hypomanic but no manic episodes (p <.05). The proportion of patients who dropped out was slightly higher among those taking lithium (16/44) compared with those taking carbamazepine (13/50), resulting in 16/44 patients (36%) on lithium treatment completing the 2 years with no episode, compared with 16/50 (32%) on carbamazepine treatment. CONCLUSION: Lithium appears to be superior in prophylactic efficacy to carbamazepine in bipolar patients not previously treated with mood stabilizers. Our results should reinforce efforts to put and maintain such patients on treatment with lithium.