Susanne Englisch

Polypharmacy in schizophrenia.

Purpose of review Although most guidelines recommend monotherapy in schizophrenia, the combined application of multiple psychotropic agents is very common, especially in treatment-refractory cases. We review the empirical basis supporting these attempts and their relevance for clinical practice. Recent findings Polypharmacy intends to address different aspects of treatment resistance, most importantly insufficient response of psychotic positive and negative symptoms, but also cognitive disturbances, affective comorbidity, obsessive–compulsive syndromes and side-effects of antipsychotic drugs. This review summarizes the current state of evidence of combined antipsychotic treatment strategies and the augmentation of antipsychotics with mood stabilizers, antidepressants and experimental substances. Summary In general, rigorous data on combination therapy in schizophrenia are rare and further randomized controlled trials, naturalistic trials and head-to-head-trials are necessary. Some evidence supports a combination of antipsychotics and antidepressants for negative symptoms and comorbid major depressive episodes. The add-on of lithium and mood stabilizers lacks compelling evidence, but might be beneficial for specific subgroups. For treatment-resistant cognitive symptoms, antipsychotic medication should be combined with cognitive remediation, as no pharmacological add-on strategy has gained convincing evidence so far. Treatment-emergent positive and/or negative symptoms under clozapine monotherapy might benefit from adding a second atypical substance.

Antiserotonergic antipsychotics are associated with obsessive-compulsive symptoms in schizophrenia.

BACKGROUND Epidemiological investigations show that up to 30% of schizophrenic patients suffer from obsessive-compulsive symptoms (OCS) associated with negative impact on the general prognosis. It has been proposed that antiserotonergic second-generation antipsychotics (SGAs) might induce OCS, but investigations of large samples integrating psychopathology, neuropsychology and psychopharmacology are missing. METHOD We stratified 70 patients with schizophrenia according to their mode of antipsychotic treatment: clozapine and olanzapine (group I) compared with aripiprazole and amisulpride (group II). The groups were matched according to age, sex, educational levels and severity of the psychotic disorder (Positive and Negative Syndrome Scale). As the primary endpoint, we evaluated OCS severity (Yale-Brown Obsessive-Compulsive Scale). RESULTS OCS were significantly more prevalent and severe in group I, in which OCS severity correlated with dosage of clozapine and duration of treatment. Pronounced cognitive deficits in group I were found in visuospatial perception and visual memory (Wechsler Adult Intelligence Scale-Revised block design, Rey-Osterrieth Complex Figure Test), impulse inhibition (go/no-go test), higher perseveration scores (Wisconsin Card Sorting Test) and reduced set-shift abilities (Trail Making Test Part B, Set-shift Task). These cognitive domains correlated with OCS severity. CONCLUSIONS OCS in schizophrenia are associated with antiserotonergic SGA treatment, but longitudinal studies have to prove causality. Before starting treatment with antiserotonergic SGAs, specific neurocognitive domains should be evaluated, as visuospatial learning and impulse inhibition performance might allow early detection of OCS secondary to antipsychotic treatment in schizophrenia.

Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients

Patients with schizophrenia show deficits in motivation, reward anticipation and salience attribution. Several functional magnetic resonance imaging (fMRI) investigations revealed neurobiological correlates of these deficits, raising the hypothesis of a common basis in midbrain dopaminergic signaling. However, investigations of drug-naïve first-episode patients with comprehensive fMRI tasks are still missing. We recruited unmedicated schizophrenia spectrum patients (N=27) and healthy control subjects (N=27) matched for sex, age and educational levels. An established monetary reward anticipation task in combination with a novel task aiming at implicit salience attribution without the confound of monetary incentive was applied. Patients showed reduced right ventral striatal activation during reward anticipation. Furthermore, patients with a more pronounced hypoactivation attributed more salience to neutral stimuli, had more positive symptoms and better executive functioning. In the patient group, a more differentially active striatum during reward anticipation was correlated positively to differential ventral striatal activation in the implicit salience attribution task. In conclusion, a deficit in ventral striatal activation during reward anticipation can already be seen in drug-naïve, first episode schizophrenia patients. The data suggest that rather a deficit in differential ventral striatal activation than a generally reduced activation underlies motivational deficits in schizophrenia and that this deficit is related to the aberrant salience attribution.

Stable Cognitive Deficits in Schizophrenia Patients With Comorbid Obsessive-Compulsive Symptoms: A 12-Month Longitudinal Study

BACKGROUND Amongst schizophrenia patients, a large subgroup of up to 25% also suffers from comorbid obsessive-compulsive symptoms (OCSs). The association between comorbid OCSs in these patients and neuropsychological impairment remains unclear and somewhat contradictory. Longitudinal approaches investigating the stability of OCS-associated cognitive deficits are missing. METHODS Thirty-seven patients with schizophrenia and comorbid OCSs and 43 schizophrenia patients without OCS were assessed with a comprehensive cognitive test battery and compared at baseline and, again, 12 months later. RESULTS Schizophrenia patients with comorbid OCSs showed significant pronounced deficits, with increasing effect sizes over the 12-month assessment period in specific cognitive areas such as visuospatial perception and visual memory (WAIS-R block design, Rey-Osterrieth Complex Figure Test), executive functioning (perseveration in the Wisconsin Card Sorting test), and cognitive flexibility (Trail Making test B). These cognitive domains are correlated with OCS severity and are known to be candidate cognitive domains in obsessive-compulsive disorder (OCD). CONCLUSIONS OCSs in schizophrenia is associated with specific and longitudinally stable cognitive deficits, strongly arguing for at least partially overlapping neurobiological mechanisms with OCD. Prospective studies involving patients with at-risk mental states for psychosis are necessary to decipher the interaction of cognitive impairment and the clinical manifestations of schizophrenia and OCSs. This might facilitate the definition of patients at high risk for OCSs, an early detection of subclinical levels, therapeutic interventions, and clinical monitoring.

Combined antipsychotic treatment involving clozapine and aripiprazole

Treatment resistance is considered a challenging problem of antipsychotic pharmacotherapy. In such cases, combination approaches are commonly used, for instance the add-on of aripiprazole to clozapine. This review aims at giving an overview of the present knowledge on this strategy. We performed a keyword-based screening of databases (including November 2007) and evaluated the data in a systematic manner. The courses of 94 patients were reported in 11 publications. At a mean dosage of 20.5 mg/day, aripiprazole achieved clinical improvement of psychotic symptoms and facilitated a dose reduction of clozapine from 476.7 to 425.1 mg/day. In parallel, clozapine serum levels decreased from 611 to 523 ng/ml. No pharmacokinetic interactions were reported, and clozapine-induced side effects ameliorated. However, single cases of extrapyramidal side effects occurred. The combination of clozapine and aripiprazole follows a neurobiological rationale and appears to be effective and tolerable. The results of placebo-controlled trials might allow further insight into the benefits and risks of this strategy.

Clozapine-Induced Obsessive-Compulsive Syndromes Improve in Combination With Aripiprazole

Patients with schizophrenia often experience comorbid obsessive-compulsive syndromes (OCSs). Within these patients, a significant subgroup developed secondary OCS during treatment with antiserotonergic, atypical antipsychotic agents such as clozapine. Although cognitive behavioral therapy and antiobsessive antidepressants brought up inconsistent results, in some cases, dose reductions of clozapine in combination approaches were able to alleviate OCS. One suggestive agent for antiobsessive add-on treatment is aripiprazole, a partial agonist at dopamine and serotonin receptors.Here, we summarize the courses of 7 patients (6 men; mean age, 37 years; mean duration of psychotic illness, 17 years). They had been treated with clozapine for 9 years. The distressing and treatment-resistant comorbidity with OCS emerged approximately 4 years after the start of clozapine therapy. During combined treatment with mean doses of 22.9 mg of aripiprazole for 9.7 weeks, we assessed a small yet statistically not significant improvement of the psychotic disorder, whereas a marked reduction of obsessions and significant improvements of compulsions could be observed. The mean total Yale Brown Obsessive Compulsive Rating Scale decreased from 18.7 to 12.4 (P = 0.003).These data support the findings of 2 previous case reports and point toward an antiobsessive potency of aripiprazole. The relevant disabling comorbidities of psychosis and OCS need further investigation with multimodal neurobiological approaches. The proposed strategy should be further evaluated in prospective controlled trials with severity of comorbid OCS as a primary end point.

Reduced activation in ventral striatum and ventral tegmental area during probabilistic decision-making in schizophrenia

Patients with schizophrenia suffer from deficits in monitoring and controlling their own thoughts. Within these so-called metacognitive impairments, alterations in probabilistic reasoning might be one cognitive phenomenon disposing to delusions. However, so far little is known about alterations in associated brain functionality. A previously established task for functional magnetic resonance imaging (fMRI), which requires a probabilistic decision after a variable amount of stimuli, was applied to 23 schizophrenia patients and 28 healthy controls matched for age, gender and educational levels. We compared activation patterns during decision-making under conditions of certainty versus uncertainty and evaluated the process of final decision-making in ventral striatum (VS) and ventral tegmental area (VTA). We replicated a pre-described extended cortical activation pattern during probabilistic reasoning. During final decision-making, activations in several fronto- and parietocortical areas, as well as in VS and VTA became apparent. In both of these regions schizophrenia patients showed a significantly reduced activation. These results further define the network underlying probabilistic decision-making. The observed hypo-activation in regions commonly associated with dopaminergic neurotransmission fits into current concepts of disrupted prediction error signaling in schizophrenia and suggests functional links to reward anticipation. Forthcoming studies with patients at risk for psychosis and drug-naive first episode patients are necessary to elucidate the development of these findings over time and the interplay with associated clinical symptoms.

Augmentation with pregabalin in schizophrenia.

Anxiety is a core symptom of schizophrenia that elicits significant subjective burden of disease and contributes to treatment resistance in schizophrenia. Anxious syndromes might be attributed to incompletely remitted delusions, the negative syndrome, depressive episodes, panic attacks, social phobia, avoidance after hospitalization, and down-tapering of benzodiazepine medication. Pregabalin, an antagonist at the alpha2delta subunit of voltage-gated Ca channels, modulates several neurotransmitter systems and was found to alleviate anxiety in different mental disorders. In schizophrenia, this treatment option has not been evaluated before.Here, we report a case series of 11 schizophrenic patients who had treatment-resistant anxiety and received augmentation with pregabalin. This observational analysis reveals that the strategy was able to significantly reduce scores on the Hamilton anxiety scale; furthermore, we observed improvements of psychotic positive and negative symptoms and mood as assessed by Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, and Calgary Depression Scale for Schizophrenia. After augmentation, both a complete discontinuation of concomitant benzodiazepine treatment as well as a dose reduction of antipsychotics could be achieved. We did not observe pharmacokinetic interactions or adverse events.These observations suggest that treating anxious syndromes in schizophrenia with pregabalin can be effective and tolerable. Further investigations should differentiate schizophrenic subsyndromes of anxiety and evaluate benefits and risks of pregabalin in comparison to placebo and active competitors.

Differential effects of antipsychotic agents on obsessive–compulsive symptoms in schizophrenia: a longitudinal study

Indirect evidence supports the assumption that antiserotonergic second-generation antipsychotics (SGA) induce and aggravate obsessive–compulsive symptoms (OCS) in schizophrenia. However, multimodal studies assessing the long-term interaction of pharmacotherapy and psychopathology are missing. Over 12 months, we followed-up 75 schizophrenia patients who were classified into two groups according to antipsychotic treatment: clozapine or olanzapine (group I) versus aripiprazole or amisulpride (group II). We applied the Yale Brown Obsessive Compulsive Scale (YBOCS) and investigated between-group changes over time as the primary endpoint. Group I showed markedly higher YBOCS scores at both time points. Repeated measure analyses of variance (ANOVAs) revealed significant interaction effects of group and time (per protocol sample (PP): p=0.006). This was due to persistently high OCS severity within group I, and decreasing YBOCS scores within group II. OCS severity correlated significantly with the negative and general psychopathology subscales of the Positive and Negative Syndrome Scale (PANSS), as well as with depressive symptoms. The progressive differences in OCS severity between our groups support the assumption of differential pharmacodynamic effects on comorbid OCS in schizophrenia. Further studies should address the pathogenetic mechanism, define patients at risk and facilitate early detection as well as therapeutic interventions.

Treatment-resistant schizophrenia: Evidence-based strategies

Treatment-resistant symptoms complicate the clinical course of schizophrenia, and a large proportion of patients do not reach functional recovery. In consequence, polypharmacy is frequently used in treatment-refractory cases, addressing psychotic positive, negative and cognitive symptoms, treatment-emergent side effects caused by antipsychotics and comorbid depressive or obsessive-compulsive symptoms. To a large extent, such strategies are not covered by pharmacological guidelines which strongly suggest antipsychotic monotherapy. Add-on strategies comprise combinations of several antipsychotic agents and augmentations with mood stabilizers; moreover, antidepressants and experimental substances are applied. Based on the accumulated evidence of clinical trials and meta-analyses, combinations of clozapine with certain second-generation antipsychotic agents and the augmentation of antipsychotics with antidepressants seem recommendable, while the augmentation with mood stabilizers cannot be considered superior to placebo. Forthcoming investigations will have to focus on innovative pharmacological agents, the clinical spectrum of cognitive deficits and the implementation of cognitive behavioral therapy.