Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

[Homelessness and mental illnesses]. / Wohnungslosigkeit und seelische Erkrankungen.

Homelessness is an expression of marked social exclusion phenomena and often particularly affects people with mental disorders. Mental disorders often precede the onset of homelessness but can also be a result of homelessness. Different forms of therapeutic and social support interventions have been evaluated in various countries, predominantly with an outreach treatment approach. These interventions were often combined with low threshold availability of housing programs. These showed positive effects on housing stability and reduction of psychiatric symptoms but not in reduction of substance use disorders. Peer support strategies and the use of digital media are possible options for future therapeutic strategies.

[Obsessive-Compulsive Symptoms in a Sample of Patients with Chronic Schizophrenia Under Clozapine Treatment]. / Zwangssymptome bei chronisch erkrankten Patienten mit einer Schizophrenie unter Clozapintherapie.

Background: There is a high prevalence of obsessive-compulsive symptoms (OCS) in patients with schizophrenia. Antipsychotic treatment, especially duration and type of substance, is suspected to increase or even cause OCS. Methods: We examined in a naturalistic cross-sectional study the severity of OCS (Obsessive-Compulsive Inventory - Revised) and the incidence of obsessive-compulsive disorder (OCD) according to ICD-10 criteria in 70 patients with schizophrenia. 26 patients were treated with clozapine and 44 patients were treated with another second-generation antipsychotic (SGA). After group matching, the two groups did not differ significantly in age, gender, duration of illness, treatment duration with the current antipsychotic substance and chlorpromazine-equivalent dosage. Results: Patients treated with Clozapine showed a significantly higher rate of OCD (χ2 = 7.304, p = 0.007) and a significantly higher severity of OCS (t = 2.216, p = 0.037) compared to patients treated with another SGA. For the whole sample, duration of treatment with the current antipsychotic medication correlated significantly (p = 0.033, r = 0.323) with the severity of OCS, controlled for duration of illness. However, there was no significant correlation between severity of OCS and duration of illness, controlled for duration of treatment with the current antipsychotic substance. Discussion: Our data suggest an interrelation between the development of OCS or OCD and antipsychotic treatment, especially clozapine. Thereby, duration of treatment is correlated with the severity of OCS, irrespective of the duration of illness.

Neural alterations of fronto-striatal circuitry during reward anticipation in euthymic bipolar disorder.

BACKGROUND: Bipolar disorder (BD), with the hallmark symptoms of elevated and depressed mood, is thought to be characterized by underlying alterations in reward-processing networks. However, to date the neural circuitry underlying abnormal responses during reward processing in BD remains largely unexplored. The aim of this study was to investigate whether euthymic BD is characterized by aberrant ventral striatal (VS) activation patterns and altered connectivity with the prefrontal cortex in response to monetary gains and losses. METHOD: During functional magnetic resonance imaging 20 euthymic BD patients and 20 age-, gender- and intelligence quotient-matched healthy controls completed a monetary incentive delay paradigm, to examine neural processing of reward and loss anticipation. A priori defined regions of interest (ROIs) included the VS and the anterior prefrontal cortex (aPFC). Psychophysiological interactions (PPIs) between these ROIs were estimated and tested for group differences for reward and loss anticipation separately. RESULTS: BD participants, relative to healthy controls, displayed decreased activation selectively in the left and right VS during anticipation of reward, but not during loss anticipation. PPI analyses showed decreased functional connectivity between the left VS and aPFC in BD patients compared with healthy controls during reward anticipation. CONCLUSIONS: This is the first study showing decreased VS activity and aberrant connectivity in the reward-processing circuitry in euthymic, medicated BD patients during reward anticipation. Our findings contrast with research supporting a reward hypersensitivity model of BD, and add to the body of literature suggesting that blunted activation of reward processing circuits may be a vulnerability factor for mood disorders.

Empathy in adults with clinical or subclinical depressive symptoms.

BACKGROUND: Depression is associated with problems in social functioning. Impaired empathic abilities might underlie this association. Empathy is a multidimensional construct and involves both affective and cognitive processes. We reviewed the literature to find out to what extent depression may be associated with abnormal levels of affective and cognitive empathy. We also explored potential gender differences in these associations. METHODS: We used PsycInfo and Medline to conduct a systematic review of all studies on empathy and depression conducted in individuals with a primary diagnosis of major depressive disorder (MDD; patient samples) or in individuals with primarily subclinical depressive symptoms (analog samples). RESULTS: Thirty-seven studies met the inclusion criteria. The results indicated that depression was related to one type of affective empathy. Specifically, depression was related to high levels of empathic stress but not to abnormal empathic concern. Further, depression was related to limited cognitive empathy, as indicated by poor perspective taking, theory of mind, and empathic accuracy. LIMITATIONS: Few studies have considered the variable gender in their design and analyses. Between and within study variation in demographic and clinical variables limits the interpretation of results. Self-report measures of empathy are subjective and vulnerable to bias. Poor performance on the more objective laboratory tasks might partially be explained by the broader cognitive deficits commonly observed in depression. Lastly, because all studies used a cross-sectional design, causality is difficult to establish. CONCLUSIONS: Empathic abilities may be impaired in depression. The relation between empathy, depression, and gender is unclear. Future studies could use implicit and more ecologically valid measures of empathy. Insight into impaired empathy in depression may not only help explain poor social functioning in MDD but also benefit clinician-patient interactions.

Effect of balloon material and inflation strategy on arterial trauma and mechanisms of percutaneous transluminal coronary angioplasty as determined by intracoronary ultrasound.

Twenty-three patients were randomized to a minimally invasive strategy or to standard percutaneous transluminal coronary angioplasty followed by intracoronary ultrasound. There was no difference in intracoronary ultrasound-determined dissection after the procedure in the 2 groups, and the mechanism of lumen enlargement by percutaneous transluminal coronary angioplasty in both groups predominantly was due to vessel stretch.

Intracoronary ultrasound: insights into mechanisms and results of coronary interventions.

Intracoronary ultrasound imaging is a modality which allows in vivo cross-sectional visualization of coronary arteries similar to that obtained by pathology. Compared with coronary angiography, intracoronary ultrasound provides more detail on plaque morphology and topography and more accurate quantification of lumen and plaque area. Thus, it has evolved into a valuable research tool. For example, intracoronary ultrasound imaging has increased understanding of the mechanisms of action of balloon angioplasty and new interventions such as atherectomy and laser treatment. It may prove to have clinical utility by helping to individualize device selection and sizing and by assessing treatment results more accurately. Coronary imaging may be performed at low risk. Future developments will include smaller catheters, combined ultrasound and therapeutic catheters, and three-dimensional reconstruction of images.

The use of the Tracker catheter as a guidewire support device in angioplasty of angulated and tortuous circumflex coronary arteries.

Marked angulation and tortuosity of the coronary arteries, particularly the circumflex, can limit coronary angioplasty. Despite the use of adequate guide catheter support and high performance guidewires, it is often difficult or even impossible to reach the distal segment of the target vessel with the guidewire. We describe three cases of successful complex circumflex coronary artery angioplasty where guidewire advancement through proximal angulated and tortuous anatomy was facilitated by the Tracker-18 Hi-Flow catheter after failure of conventional angioplasty hardware.

Thromboembolus traversing a patent foramen ovale: resolution with anticoagulation.

This case report documents echocardiographically a thromboembolus actively traversing a patent foramen ovale in a 72-year-old man with a dilated cardiomyopathy and systemic lupus erythematosis complicated by chronic low-grade disseminated intravascular coagulation and multiple lower extremity deep venous thromboses. With intravenous heparin therapy, there was apparent resolution of this thromboembolus without clinical evidence of systemic embolization.

Bulk wave membrane quartz resonators fabricated by a hollow cathode RF plasma etching technique.

A hollow cathode maskless plasma etching method for fabrication of thin quartz membranes is presented. A special geometric arrangement of electrodes and substrates allows the complete plasma structure (plasma sheath, bulk plasma) to be transferred to the substrate area during the etching process. The process has successfully been used in preparing thin quartz membranes with plane-convex and plane-parallel shape, and thicknesses of less than 5 mum. Vibration modes in these thin quartz membranes are calculated using the method of equivalent resonant radius. The membranes are used for realization of bulk acoustic wave resonators at fundamental frequencies above 60 MHz. Good agreement between theoretical and experimental characteristics is achieved.

Double cardiomyopathy: coexistent cardiac amyloidosis and hypertrophic obstructive cardiomyopathy.

A combination of hypertrophic obstructive cardiomyopathy (HOCM) and cardiac amyloidosis in the same patient is very rare. Clinical diagnosis could be extremely difficult and may require myocardial biopsy. We are reporting a patient with this combination who was referred to our institution because of features of HOCM based on clinical, echocardiographic and Doppler criteria. Cardiac amyloidosis was only recognized after myocardial biopsy that failed to reveal evidence of HOCM. Only after the patient expired from severe, intractable heart failure did the autopsy findings confirm the association of HOCM. We believe that the combination of the two cardiomyopathic processes is very rare and makes treatment extremely difficult.

Adriamycin combined with 10-day Ara-C, vincristine, and prednisone (10-day ADOAP) in the treatment of adult acute leukemia patients under fifty years of age. A Southwest Oncology Group Study.

In a twelve-month period, 56 consecutive patients with acute leukemia, aged 15-50, were treated by administration of a 10-day continuous infusion of Ara-C in combination with adriamycin, oncovin and prednisone (10 day ADOAP). Of 50 evaluable patients, there were 39 complete remissions (78%) with a median remission duration of 71 weeks. After adjustment for age and other known prognostic factors, the complete remission rate is still 10% higher than that found using a similar regimen without adriamycin.

Prevalence of clinical mitral-valve prolapse in 1169 young women.

Eleven hundred and sixty-nine young women were prospectively examined for the presence of mitral-valve prolapse as manifested by midsystolic non-ejection click or late systolic murmur (or both). Of the 1169 women 74 (6.3%) had physical findings consistent with mitral-valve prolapse. Sixty-eight of the 74 (92%) had midsystolic non-ejection click, and in 57 the click was accompanied by a late systolic murmur. In six (8%) only a late systolic murmur was heard. Echocardiography on all patients with clinical diagnosis of mitral-valve prolapse showed patterns of prolapse in 60 of 74 (81%). Fourteen (19%) had negative echocardiograms. We conclude that mitral-valve prolapse is clinically present in approximately 6.3% of otherwise healthy young women.