Increased orbitofrontal cortex activation associated with “pro-obsessive” antipsychotic treatment in patients with schizophrenia

Background

Patients with schizophrenia have an approximately 10-fold higher risk for obsessive–compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms.

Methods

To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole). We used an fMRI approach, applying a go/no-go task assessing inhibitory control and an n-back task measuring working memory.

Results

We enrolled 21 patients in group I and 19 patients in group II. Groups did not differ regarding age, sex, education or severity of psychotic symptoms. Frequency and severity of OCS were significantly higher in group I and were associated with pronounced deficits in specific cognitive abilities. Whereas brain activation patterns did not differ during working memory, group I showed significantly increased activation in the orbitofrontal cortex (OFC) during response inhibition. Alterations in OFC activation were associated with the severity of obsessions and mediated the association between SGA treatment and co-occurring OCS on a trend level.

Limitations

The main limitation of this study is its cross-sectional design.

Conclusion

To our knowledge, this is the first imaging study conducted to elucidate SGA effects on neural systems related to OCS. We propose that alterations in brain functioning reflect a pathogenic mechanism in the development of SGA-induced OCS in patients with schizophrenia. Longitudinal studies and randomized interventions are needed to prove the suggested causal interrelations.     

The effects of bilateral stimulation of the subthalamic nucleus on heart rate variability in patients with Parkinson’s disease

The beneficial effects of subthalamic nucleus deep brain stimulation (STN-DBS) on motor symptoms and quality of life in Parkinson’s disease (PD) are well known, but little is known of the effects on autonomic function. Diffusion of current during stimulation of the STN may simultaneously involve the motor and nonmotor, limbic and associative areas of the STN. The aims of this study were to examine whether STN stimulation affects functions of the autonomic nervous system and, if so, to correlate the effects with the active contacts of electrodes in the STN. Eight PD patients with good motor control and quality of sleep after STN-DBS surgery were recruited. All patients had two days of recordings with portable polysomnography (PSG) (first night with stimulation “on” and second night “off”). From the PSG data, the first sleep cycle of each recording night was defined. Heart rate variability (HRV) was analyzed between the same uninterrupted periods of the two sleep nights. In addition, the optimal electrode positions were defined from postoperative MRI studies, and the coordinates of active contacts were confirmed. HRV spectral analysis showed that only low-frequency (LF)/high-frequency (HF) power was significantly activated in the stimulation “on” groups (P = 0.011). There was a significant negative correlation between power change of LF/HF and electrode position lateral to the midcommissural point (ρ = 0.857, P = 0.007) These results demonstrate that STN-DBS can enhance sympathetic regulation; the autonomic response may be due to electrical signals being distributed to limbic components of the STN or descending sympathetic pathways in the zona incerta.     

A translational research approach to poor treatment response in patients with schizophrenia: clozapine–antipsychotic polypharmacy

Poor treatment response in patients with schizophrenia is an important clinical problem, and one possible strategy is concurrent treatment with more than one antipsychotic (polypharmacy). We analyzed the evidence base for this strategy using a translational research model focused on clozapine–antipsychotic polypharmacy (CAP). We considered 3 aspects of the existing knowledge base and translational research: the link between basic science and clinical studies of efficacy, the evidence for effectiveness in clinical research and the implications of research for the health care delivery system. Although a rationale for CAP can be developed from receptor pharmacology, there is little available preclinical research testing these concepts in animal models. Randomized clinical trials of CAP show minimal or no benefit for overall severity of symptoms. Most studies at the level of health services are limited to estimates of CAP prevalence and some suggestion of increased costs. Increasing use of antipsychotic polypharmacy in general may be a factor contributing to the under-utilization of clozapine and long delays in initiating clozapine monotherapy. Translational research models can be applied to clinical questions such as the value of CAP. Better linkage between the components of translational research may improve the appropriate use of medications such as clozapine in psychiatric practice.     

Effects of depression and melatonergic antidepressant treatment alone and in combination with sedative–hypnotics on heart rate variability: Implications for cardiovascular risk

Objectives: To examine heart rate variability (HRV) in unmedicated patients with major depressive disorder (MDD) and its changes after treatment with agomelatine alone and in combination with sedative–hypnotics.

Methods: We recruited 152 physically healthy, unmedicated patients with MDD and 472 age- and sex-matched healthy volunteers. Frequency-domain measures of HRV were obtained during enrolment for all participants and again for MDD patients after 6 weeks of treatment with agomelatine alone and combining sedative–hypnotics.

Results: Compared to the controls, unmedicated patients exhibited significantly lower mean R-R intervals, low-frequency (LF) HRV, and high-frequency (HF) HRV, but higher LF/HF ratios. Fifty-six and 49 patients successfully completed agomelatine monotherapy and the combination therapy of agomelatine and sedative–hypnotics, respectively. Between-group analyses showed significant treatment-by-group interactions for LF-HRV, HF-HRV and LF/HF ratio. The results showed a significant increase in HF-HRV after agomelatine monotherapy, a significant decrease in LF-HRV and HF-HRV, and a increase in the LF/HF ratio after combination therapy.

Conclusions: MDD patients had reduced HRV, and the patterns of HRV changes differed between patients treated with agomelatine alone and in combination with sedative–hypnotics. Clinicians should consider HRV effects when adding sedative–hypnotics to agomelatine, which is important for depressed patients who already have decreased cardiac vagal tone.     

Do antipsychotic medications decrease the risk of suicide in patients with schizophrenia?

The lifetime risk of suicide in persons with schizophrenia is much greater than that in the general population. The role of antipsychotic medications in decreasing suicide risk in schizophrenia has been little studied, and results often appear inconclusive and even confusing when issues such as dose-response effect are examined. Yet, evidence exists that both the traditional and newer antipsychotic medications reduce the risk of suicide and suicide attempts in schizophrenia. Because side effects are potentially significant risk factors in suicide, considerable incentive exists to examine whether newer antipsychotic agents that have a lower incidence of extrapyramidal side effects offer greater safety for this population.     

Sensorimotor dysfunction of grasping in schizophrenia: a side effect of antipsychotic treatment?

BACKGROUND: Antipsychotic treatment in schizophrenia is frequently associated with extrapyramidal side effects. Objective behavioural measures to evaluate the severity of extrapyramidal side effects in the clinical setting do not exist. OBJECTIVES: This study was designed to investigate grasping movements in five drug naive and 13 medicated subjects with schizophrenia and to compare their performance with that of 18 healthy control subjects. Deficits of grip force performance were correlated with clinical scores of both parkinson-like motor disability and psychiatric symptom severity METHODS: Participants performed vertical arm movements with a handheld instrumented object and caught a weight that was dropped into a handheld cup either expectedly from the opposite hand or unexpectedly from the experimenter's hand. The scaling of grip force and the temporospatial coupling between grip and load force profiles was analysed. The psychiatric symptom severity was assessed by the positive and negative symptom score of schizophrenia and the brief psychiatric rating scale. Extrapyramidal symptoms were assessed by the unified Parkinson's disease rating scale. RESULTS: Drug naive subjects with schizophrenia performed similar to healthy controls. In contrast, medicated subjects with schizophrenia exhibited excessive grip force scaling and impaired coupling between grip and load force profiles. These performance deficits were strongly correlated with the severity of both extrapyramidal side effects related to antipsychotic therapy and negative symptoms related to the underlying pathology. CONCLUSIONS: These data provide preliminary evidence that deficits of sensorimotor performance in schizophrenia are, at least in part, related to the side effects of antipsychotic treatment. The investigation of grasping movements may provide a sensitive measure to objectively evaluate extrapyramidal side effects related to antipsychotic therapy.     

Insight in schizophrenia–course and predictors during the acute treatment phase of patients suffering from a schizophrenia spectrum disorder

BackgroundTo analyse insight of illness during the course of inpatient treatment, and to identify influencing factors and predictors of insight.MethodsInsight into illness was examined in 399 patients using the item G12 of the Positive and Negative Syndrome Scale (“lack of insight and judgement”). Ratings of the PANSS, HAMD, UKU, GAF, SOFAS, SWN-K and Kemp's compliance scale were performed and examined regarding their potential association with insight. The item G12 was kept as an ordinal variable to compare insight between subgroups of patients.ResultsAlmost 70% of patients had deficits in their insight into illness at admission. A significant improvement of impairments of insight during the treatment (p < 0.0001) was observed. At admission more severe positive and negative symptoms, worse functioning and worse adherence were significantly associated with poorer insight. Less depressive symptoms (p = 0.0004), less suicidality (p = 0.0218), suffering from multiple illness-episodes (p < 0.0001) and worse adherence (p = 0.0012) at admission were identified to be significant predictors of poor insight at discharge.ConclusionThe revealed predictors might function as treatment targets in order to improve insight and with it outcome of schizophrenia.     

Long-term changes in heart rate variability in elementary school–aged children with sleep-disordered breathing

ObjectiveSleep-disordered breathing (SDB) in adults and children has been associated with reduced heart rate variability (HRV) indicative of autonomic dysfunction, which in turn is associated with an increased risk for cardiovascular morbidity. However, the long-term effects of pediatric SDB that has either resolved or remains unresolved on HRV are unknown.MethodsForty Children with previously diagnosed SDB and 20 non snoring controls underwent repeat overnight polysomnography (PSG) four years after the original diagnosis. At follow-up, children aged 11 to 16 years were categorized into resolved (absence of snoring and obstructive apnea hypopnea index [OAHI] ⩽ 1) or unresolved (continued to snore or had an OAHI > 1) groups. HRV was assessed using power spectral analysis for each sleep stage.ResultsThere were no group differences in age, sex or body mass index (BMI) z score. Both the resolved and unresolved SDB groups showed significant improvement in OAHI. The control, resolved, and unresolved groups all showed a significant reduction in total power (P < .001), low-frequency (LF) power (P < .05), high-frequency (HF) power (P < .001), and an increase in the LF/HF ratio (P < .001) from baseline to follow-up in all sleep stages.ConclusionsHRV did not differ between non snoring children and children with resolved and unresolved SDB four years after initial diagnosis, concomitant with a significant reduction in OAHI in both SDB groups. All groups demonstrated a decrease in HRV from baseline to follow-up which may reflect an age-related phenomenon in these children.     

Interventions to improve adherence to antipsychotic medication in patients with schizophrenia–A review of the past decade

ObjectiveNonadherence to antipsychotic medication is highly prevalent in patients with schizophrenia and has a deleterious impact on the course of the illness. This review seeks to determine the interventions that were examined in the past decade to improve adherence rates.MethodThe literature between 2000 and 2009 was searched for randomized controlled trials which compared a psychosocial intervention with another intervention or with treatment as usual in patients with schizophrenia.ResultsFifteen studies were identified, with a large heterogeneity in design, adherence measures and outcome variables. Interventions that offered more sessions during a longer period of time, and especially those with a continuous focus on adherence, seem most likely to be successful, as well as pragmatic interventions that focus on attention and memory problems. The positive effects of adapted forms of Motivational Interviewing found in earlier studies, such as compliance therapy, have not been confirmed.ConclusionNonadherence remains a challenging problem in schizophrenia. The heterogeneity of factors related to nonadherence calls for individually tailored approaches to promote adherence. More evidence is required to determine the effects of specific interventions.     

Blood–cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment

Blood–cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined.     

Assessment of autonomic nervous system function in patients with Behçet' s disease by spectral analysis of heart rate variability

The purpose of this study was to evaluate the autonomic nervous system (ANS) function in patients with Behcet's disease by using power spectral analysis of heart rate variability (HRV). The study population consisted of 71 patients with Behcet's disease, and 26 normal volunteers. HRV was measured by power spectral analysis in supine and standing position. In supine position, Behcet's patients had increased low frequency component in absolute (LF) and normalized units (LF nU) but had lower values of high frequency component in absolute (HF) and normalized units (HF nU) than the controls (P < 0.05). In standing position, higher values were obtained in LF and LF nU but lower values of HF and HF nU in Behcet's patients than controls (P < 0.05). LF/HF was significantly higher in patients both in supine (2.5 +/- 1.0 vs. 1.2 +/- 0.8, P = 0.001) and standing (21.9 +/- 7 vs. 1.8 +/- 0.3, P < 0.001) positions. Our data suggest that patients with Behcet's disease may have asymptomatic ANS dysfunction, which is in the form of increased sympathetic and decreased parasympathetic modulation, and power spectral analysis of HRV is beneficial in assessing the ANS function.     

Femoxetine in the treatment of patients with depressive illness–a randomized comparison with amitriptyline

The significance of the antidepressants' serotonin-potentiating properties in relationship to the therapeutic effect has been one of the key research areas within depression during the last decades.

On this basis a number of drugs with more selective influence on the serotonin system has been developed and the following study is a controlled clinical evaluation of femoxetine, a phenylpiperidine derivative with potent serotonin-potentiating properties in patients suffering from a depressive illness.     

Is heart rate variability related to gait impairment in patients with Parkinson's disease? A pilot study

Background and purposeImpairments in gait and autonomic function are common in patients with Parkinson's disease (PD). These are likely independent symptoms, based on different etiologic mechanisms. However, a few recent reports have observed an association between motor function, in particular gait impairment, and autonomic function in PD. In those studies, the Unified Parkinson's Disease Rating Scale (UPDRS) was used to evaluate gait and motor function. The present study was performed to further examine this putative relationship using quantitative measures of autonomic function and gait in order to shed light on the underlying pathophysiology of these symptoms.MethodsNine healthy young, 15 healthy elderly and 18 PD patients were studied. Heart rate variability (HRV) measures were collected during rest. Gait speed, swing time and swing time variability were measured during a 1-min walk at comfortable speed. The motor portion of the UPDRS was also evaluated in all subjects.ResultsHRV values were highest in the young adults, intermediate in the healthy elderly controls, and lowest in the PD patients. Gait measures tended to deteriorate with age and were significantly worse in the PD patients, compared to the elderly controls. HRV was not correlated with any measure of gait performance (p > 0.129) nor with the UPDRS-motor score (p > 0.147).Discussion and conclusionsThe present findings support the idea that gait and autonomic function impairments co-exist in PD, but their etiology is based on distinct pathophysiological pathways, with minimal overlap.     

Anxious–depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy?

Schizophrenia patients frequently manifest concurrent anxiety and depressive symptoms. Such features exhibit prognostic relevance (i.e. patient morbidity and mortality). Despite this, they remain relatively unstudied and are not universally viewed as therapeutic targets. Conventional neuroleptic agents may not improve these symptoms and may actually worsen them. However, with the introduction of novel pharmacological agents for the treatment of schizophrenia, there is reason to believe that a wider spectrum of symptomatology may be treatment responsive. In this post hoc analysis of the Brief Psychiatric Rating Scale anxiety–depression cluster, olanzapine therapy was associated with a significantly greater baseline-to-end-point improvement in the cluster compared with haloperidol therapy among 1996 randomized, double-blind subjects. Moreover, the olanzapine treatment-effect advantage included both direct (mood symptoms) and indirect (positive, negative, and extrapyramidal symptoms) elements. This study concluded that the novel pharmacology of olanzapine delivered greater therapeutic activity in anxious and depressive symptoms accompanying schizophrenia than did the conventional dopamine D₂ antagonist haloperidol.     

Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect?

CONTEXT: Cognitive impairment in schizophrenia is frequent, involves multiple domains, and is enduring. Numerous recent clinical trials have suggested that second-generation antipsychotic medications significantly enhance cognition in schizophrenia. However, none of these studies included healthy controls undergoing repeated testing to assess the possibility that improvements might reflect simple practice effects. OBJECTIVE: To report the results on cognition of a randomized comparison of 2 widely prescribed second-generation antipsychotic medications, olanzapine and risperidone, in patients with first-episode schizophrenia and a healthy control group. DESIGN: Randomized clinical trial. SETTING: Hospital-based research units. Patients A total of 104 participants with first-episode schizophrenia and 84 healthy controls. MAIN OUTCOME MEASURES: Cognitive assessment of all study participants occurred at baseline, 6 weeks later, and 16 weeks later. Neurocognitive tests included measures of working memory and attention, speed, motor function, episodic memory, and executive function. RESULTS: No differential drug effects were observed. Of 16 cognitive measures, 9 demonstrated improvement over time and only 2 demonstrated greater rates of change than those observed in the healthy control group undergoing repeated assessment. The composite effect size for cognitive change was 0.33 in the healthy control group (attributed to practice) and 0.36 in the patients with first-episode schizophrenia. Improvements in cognition in the first-episode schizophrenia group could not be accounted for by medication dose, demographic variables, or intellectual level. CONCLUSIONS: The cognitive improvements observed in the trial were consistent in magnitude with practice effects observed in healthy controls, suggesting that some of the improvements in cognition in the first-episode schizophrenia group may have been due to practice effects (ie, exposure, familiarity, and/or procedural learning). Our results also indicated that differential medication effects on cognition were small. We believe that these findings have important implications for drug discovery and the design of registration trials that attempt to demonstrate cognitive enhancement.     

Short-term deceleration capacity of heart rate: a sensitive marker of cardiac autonomic dysfunction in idiopathic Parkinson’s disease

Clinical Autonomic Research - Cardiac autonomic dysfunction in idiopathic Parkinson’s disease (PD) manifests as reduced heart rate variability (HRV). In the present study, we explored the...     

Multisensory integration of emotionally valenced olfactory–visual information in patients with schizophrenia and healthy controls

Background

Patients with schizophrenia frequently have deficits in social cognition, and difficulties in the discrimination of emotional facial expressions have been discussed as an important contributing factor. We investigated whether this impairment is aggravated by difficulties relating the observed facial expression to contextual information, as is often provided by emotionally valenced crossmodal stimulation.

Methods

We investigated the effects of odorant primes on the accuracy and speed of emotional face recognition. Healthy controls and patients with schizophrenia were exposed to 2-second odorant stimuli: vanillin (pleasant), ambient air (neutral) and hydrogen sulfide (unpleasant). The odours were followed by an emotional face recognition task, in which participants determined if a face showed happiness, disgust or neutral affect.

Results

Controls showed improved performance in the categorization of disgusted faces after all types of odour stimulation irrespective of the emotional valence. However, in controls, the response time for happy faces was slower after presentation of any odour. Schizophrenia patients showed an attenuated effect of olfactory priming on disgust recognition, which resulted in the increased performance differences between the groups. This effect was particularly strong for the unpleasant odour.

Limitations

The study design did not allow us to fully differentiate between the effects of perceived odour intensity and valence. A possible contribution of cognitive deficits on the observed effects should be investigated in future studies.

Conclusion

Our results provide novel evidence for a special connection between the presentation of odorant cues and the accuracy of recognition of disgusted faces in healthy controls. This recognition advantage is disturbed in patients with schizophrenia and appears to contribute to the observed deficit in emotional face recognition.