Cognitive behavioural therapy for insomnia (CBT-I) in schizophrenia and schizoaffective disorder: protocol for a randomised controlled trial.

INTRODUCTION: Insomnia is a common symptom among patients with schizophrenia and schizoaffective disorder, negatively impacting symptom severity, functioning and well-being; however, it is rarely the direct focus of treatment. The main recommended treatment for insomnia is cognitive behavioural therapy (CBT-I). There is some evidence that CBT-I can also be used to treat insomnia in patients with schizophrenia, but only a few randomised controlled trials (RCTs) have been published. The aim of this ongoing RCT is to determine whether we can alleviate symptoms of insomnia and improve the quality of life in patients with schizophrenia and schizoaffective disorder through CBT-I delivered via the internet or in a group mode. METHODS AND ANALYSES: The aim of this study is to recruit 84-120 outpatients from the Psychosis Clinics of Helsinki University Hospital and the City of Helsinki Health Services. The main inclusion criteria are a diagnosis of schizophrenia or schizoaffective disorder and self-reported sleep problems. The study will be performed on a cyclic basis, with a target of 12-24 patients per cycle. Participants are randomly assigned into three groups: (1) a group receiving only treatment as usual (TAU), (2) internet-based individual therapy for insomnia (iCBT-I)+TAU or (3) group therapy for insomnia (GCBT-I) conducted via a virtual platform+TAU. The primary outcome measures are quantitative changes in the Insomnia Severity Index score and/or changes in health-related quality of life using the 15D quality of life measure. Secondary outcomes include self-reported variables for sleep, health, stress and the severity of psychotic and depressive symptoms; objective outcomes include actigraphy and bed sensor data to evaluate circadian rhythms and motor activity. Outcome measures are assessed at baseline and after the treatment period at weeks 12, 24 and 36. ETHICS AND DISSEMINATION: The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa, Finland, approved the study protocol. The results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04144231.

The Overall Anxiety Severity and Impairment Scale as an Outcome Measure in Internet-Delivered Cognitive Behavioral Therapy for Anxiety Disorders: Observational Study.

BACKGROUND: Internet-delivered cognitive behavioral therapy (iCBT) is effective in the treatment of anxiety disorders. iCBT clinical trials use relatively long and time-consuming disorder-specific rather than transdiagnostic anxiety measurements. Overall Anxiety Severity and Impairment Scale (OASIS) is a brief self-report scale that could offer a universal, easy-to-use anxiety measurement option in disorder-specific and transdiagnostic iCBT programs. OBJECTIVE: We aimed to investigate relationships between OASIS and disorder-specific instruments in iCBT. We expected these relationships to be positive. METHODS: We investigated patients in original nationwide iCBT programs for generalized anxiety disorder (GAD), obsessive-compulsive disorder, panic disorder, and social anxiety disorder, which were administered by Helsinki University Hospital, Finland. In each program, anxiety symptoms were measured using both disorder-specific scales (the 7-item Generalized Anxiety Disorder scale, Penn State Worry Questionnaire, revised Obsessive-Compulsive Inventory, Panic Disorder Severity Scale, and Social Phobia Inventory) and by OASIS. A general linear model for repeated measures (mixed models) and interaction analysis were used for investigating the changes and relationships in the mean scores of OASIS and disorder-specific scales from the first session to the last one. RESULTS: The main effect of linear mixed models indicated a distinct positive association between OASIS and disorder-specific scale scores. Interaction analysis demonstrated relatively stable associations between OASIS and the revised Obsessive-Compulsive Inventory (F822.9=0.09; 95% CI 0.090-0.277; P=.32), and OASIS and the Panic Disorder Severity Scale (F596.6=-0.02; 95% CI -0.108 to -0.065; P=.63) from first the session to the last one, while the 7-item Generalized Anxiety Disorder scale (F4345.8=-0.06; 95% CI -0.109 to -0.017; P=.007), Penn State Worry Questionnaire (F4270.8=-0.52; 95% CI -0.620 to -0.437; P<.001), and Social Phobia Inventory (F862.1=-0.39; 95% CI -0.596 to -0.187; P<.001) interrelated with OASIS more strongly at the last session than at the first one. CONCLUSIONS: OASIS demonstrates clear and relatively stable associations with disorder-specific symptom measures. Thus, OASIS might serve as an outcome measurement instrument for disorder-specific and plausibly transdiagnostic iCBT programs for anxiety disorders in regular clinical practice.

Measurement Invariant but Non-Normal Treatment Responses in Guided Internet Psychotherapies for Depressive and Generalized Anxiety Disorders.

Assessment of treatment response in psychotherapies can be undermined by lack of longitudinal measurement invariance (LMI) in symptom self-report inventories, by measurement error, and/or by wrong model assumptions. To understand and compare these threats to validity of outcome assessment in psychotherapy research, we studied LMI, sum scores, and Davidian Curve Item Response Theory models in a naturalistic guided internet psychotherapy treatment register of 2,218 generalized anxiety disorder (GAD) patients and 3,922 depressive disorder (DD) patients (aged ≥16 years). Symptoms were repeatedly assessed by Generalized Anxiety Disorder Assessment-7 (GAD-7) or Beck Depression Inventory. The symptom self-reports adhered to LMI under equivalence testing, suggesting sum scores are reasonable proxies for disorder status. However, the standard LMI assumption of normally distributed latent factors did not hold and inflated treatment response estimates by 0.2 to 0.3 standard deviation units compared with sum scores. Further methodological research on non-normally distributed latent constructs holds promise in advancing LMI and mental health assessment.

Finnish Psychotherapy Quality Register: rationale, development, and baseline results.

BACKGROUND: The push to systematically follow treatment outcomes in psychotherapies to improve health care is increasing worldwide. To manage psychotherapeutic services and facilitate tailoring of therapy according to feedback a comprehensive and feasible data system is needed. AIMS: To describe the Finnish Psychotherapy Quality Register (FPQR), a comprehensive database on availability, quality, and outcomes of psychotherapies. METHODS: We describe the development of the FPQR and outcome for outsourced psychotherapies for adults in Helsinki and Uusimaa hospital district (HUS). Symptom severity and functioning are measured with validated measures (e.g. CORE-OM, PHQ-9, OASIS, AUDIT, and SOFAS). Questionnaires on therapeutic alliance, risks, methods, and goals are gathered from patients and psychotherapist. RESULTS: During 2018-2021, the FPQR included baseline data for 7274 unique patients and 336 psychotherapists. Response rate of measures was 85-98%. The use of the register was mandatory for the outsourced therapist of the hospital districts, and the patients were strongly recommended to fulfill the questionnaires. We report outcome for three groups of patients (n = 1844) with final/midterm data. The effect sizes for long psychotherapy (Hedge's g = 0.65 of SOFAS) were smaller than those for short psychotherapy (g = 0.75-0.91). Within three months of referral, 26-60% entered treatment depending on short- or long-term therapy. CONCLUSION: The FPQR forms a novel rich database with commensurate data on availability and outcomes of outsourced psychotherapies. It may serve as a basis for a national comprehensive follow-up system of psychosocial treatments. The Finnish system seems to refer patients with milder symptoms to more intensive treatments and achieve poorer results compared to the IAPT model in UK, Norway, or Australia.

Text Topics and Treatment Response in Internet-Delivered Cognitive Behavioral Therapy for Generalized Anxiety Disorder: Text Mining Study.

BACKGROUND: Text mining methods such as topic modeling can offer valuable information on how and to whom internet-delivered cognitive behavioral therapies (iCBT) work. Although iCBT treatments provide convenient data for topic modeling, it has rarely been used in this context. OBJECTIVE: Our aims were to apply topic modeling to written assignment texts from iCBT for generalized anxiety disorder and explore the resulting topics' associations with treatment response. As predetermining the number of topics presents a considerable challenge in topic modeling, we also aimed to explore a novel method for topic number selection. METHODS: We defined 2 latent Dirichlet allocation (LDA) topic models using a novel data-driven and a more commonly used interpretability-based topic number selection approaches. We used multilevel models to associate the topics with continuous-valued treatment response, defined as the rate of per-session change in GAD-7 sum scores throughout the treatment. RESULTS: Our analyses included 1686 patients. We observed 2 topics that were associated with better than average treatment response: "well-being of family, pets, and loved ones" from the data-driven LDA model (B=-0.10 SD/session/∆topic; 95% CI -016 to -0.03) and "children, family issues" from the interpretability-based model (B=-0.18 SD/session/∆topic; 95% CI -0.31 to -0.05). Two topics were associated with worse treatment response: "monitoring of thoughts and worries" from the data-driven model (B=0.06 SD/session/∆topic; 95% CI 0.01 to 0.11) and "internet therapy" from the interpretability-based model (B=0.27 SD/session/∆topic; 95% CI 0.07 to 0.46). CONCLUSIONS: The 2 LDA models were different in terms of their interpretability and broadness of topics but both contained topics that were associated with treatment response in an interpretable manner. Our work demonstrates that topic modeling is well suited for iCBT research and has potential to expose clinically relevant information in vast text data.

Effectiveness of mobile-delivered, therapist-assisted cognitive behavioral therapy for insomnia in nationwide routine clinical care in Finland.

STUDY OBJECTIVES: Internet-delivered cognitive behavioral therapies (iCBTs) are efficacious for insomnia. Few studies have as yet reported their effectiveness in routine care. The objective of this study was to examine the effectiveness of the new Finnish 7-session HUS Helsinki University Hospital-iCBT for Insomnia (HUS-iCBTI) program in nationwide routine care. METHODS: We studied 2,464 physician-referred patients in therapist-supported iCBTI. Treatment was free of charge for patients. The primary measure was the Insomnia Severity Index (ISI); the Patient Health Questionnaire, 4-item version (PHQ-4), and the Alcohol Use Disorders Identification Test (AUDIT-C) were also administered. RESULTS: As many as 75.4% completed the treatment, with the ISI scores declining, on average, by -7.04 points during treatment. Altogether, 91.1% of the completers improved in terms of having a lower ISI score in phase 7 than in phase 1 and 34.0% of the completers achieved remission by phase 7 (ISI score < 8); 46.0% responded to treatment (ISI-score reduction of ≥ 8 points from phase 1). The Cohen's effect size (ISI-score decline) was d = -1.449, showing a large effect. CONCLUSIONS: We observed large benefits for this publicly funded therapist-supported treatment in its naturalistic setting as a part of routine care. Effect sizes were comparable to randomized controlled trials reported earlier. HUS-iCBTI appears to be effective as a treatment for insomnia and may also reduce the risk of other adverse health consequences associated with poor sleep. CITATION: Stenberg J-H, Ritola V, Joffe G, Saarni S, Rosenström T. Effectiveness of mobile-delivered, therapist-assisted cognitive behavioral therapy for insomnia in nationwide routine clinical care in Finland. J Clin Sleep Med. 2022;18(11):2643-2651.

Internet-Delivered Cognitive Behavioral Therapy for Generalized Anxiety Disorder in Nationwide Routine Care: Effectiveness Study.

BACKGROUND: Therapist-supported, internet-delivered cognitive behavioral therapy (iCBT) is efficacious for generalized anxiety disorder (GAD), but few studies are yet to report its effectiveness in routine care. OBJECTIVE: In this study, we aim to examine whether a new 12-session iCBT program for GAD is effective in nationwide routine care. METHODS: We administered a specialized, clinic-delivered, therapist-supported iCBT for GAD in 1099 physician-referred patients. The program was free of charge for patients, and the completion time was not predetermined. We measured symptoms with web-based questionnaires. The primary measure of anxiety was the GAD 7-item scale (GAD-7); secondary measures were, for pathological worry, the Penn State Worry Questionnaire and, for anxiety and impairment, the Overall Anxiety Severity and Impairment Scale. RESULTS: Patients completed a mean 7.8 (SD 4.2; 65.1%) of 12 sessions, and 44.1% (485/1099) of patients completed all sessions. The effect size in the whole sample for GAD-7 was large (Cohen d=0.97, 95% CI 0.88-1.06). For completers, effect sizes were very large (Cohen d=1.34, 95% CI 1.25-1.53 for GAD-7; Cohen d=1.14, 95% CI 1.00-1.27 for Penn State Worry Questionnaire; and Cohen d=1.23, 95% CI 1.09-1.37 for Overall Anxiety Severity and Impairment Scale). Noncompleters also benefited from the treatment. Greater symptomatic GAD-7-measured relief was associated with more completed sessions, older age, and being referred from private or occupational care. Of the 894 patients with a baseline GAD-7 score ≥10, approximately 421 (47.1%) achieved reliable recovery. CONCLUSIONS: This nationwide, free-of-charge, therapist-supported HUS Helsinki University Hospital-iCBT for GAD was effective in routine care, but further research must establish effectiveness against other treatments and optimize the design of iCBT for GAD for different patient groups and individual patients.

Scheduled Telephone Support for Internet Cognitive Behavioral Therapy for Depression in Patients at Risk for Dropout: Pragmatic Randomized Controlled Trial.

BACKGROUND: Therapist-supported, internet-delivered cognitive behavioral therapy (iCBT) is efficient in the treatment of depression. However, the optimal mode and intensity of therapist support remain to be identified. Scheduled telephone support (STS) may improve adherence and outcomes but, as it is time- and resource-consuming, should be reserved for patients for whom the usual support may be insufficient. OBJECTIVE: This paper aims to reveal whether add-on STS for patients at risk of dropping out improves treatment adherence and symptoms in iCBT for depression. METHODS: Among patients participating in an ongoing large observational routine clinical practice study of iCBT for depression delivered nationwide by Helsinki University Hospital (HUS-iCBT), those demonstrating a ≥14-day delay in initiation of treatment received invitations to this subsidiary STS study. A total of 100 consenting patients were randomly allocated to either HUS-iCBT as usual (control group, n=50) or HUS-iCBT plus add-on STS (intervention group, n=50). Proportions of those reaching midtreatment and treatment end point served as the primary outcome; secondary outcomes were change in Beck Depression Inventory (BDI)-measured depressive symptoms and time spent in treatment. RESULTS: Add-on STS raised the proportion of patients reaching midtreatment compared with HUS-iCBT as usual (29/50, 58% vs 18/50, 36%; P=.045) and treatment end point (12/50, 24% vs 3/50, 6%; P=.02). Change in BDI score also favored add-on STS (3.63 points vs 1.1 points; P=.049), whereas duration of treatment did not differ. CONCLUSIONS: Add-on STS enhances adherence and symptom improvement of patients at risk of dropping out of iCBT for depression in routine clinical practice. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) 55123131; http://www.isrctn.com/ISRCTN55123131.

Effectiveness of internet-delivered cognitive behavioural therapy in reducing sickness absence among young employees with depressive symptoms: study protocol for a large-scale pragmatic randomised controlled trial.

INTRODUCTION: Depression is a highly prevalent condition with typical onset in early adulthood. Internet-delivered cognitive behavioural therapy (iCBT) is a promising cost-effective and more widely available alternative to face-to-face CBT. However, it is not known whether it can reduce sickness absence in employees showing depressive symptoms. The randomised controlled trial component of the DAQI (Depression and sickness absence in young adults: a quasi-experimental trial and web-based treatment intervention) project aims to investigate if iCBT is effective in reducing sickness absence compared with care as usual (CAU) among young employees with depressive symptoms in primary care provided in an occupational health setting. METHODS AND ANALYSIS: This study will use a randomised controlled single-centre service-based trial of an existing iCBT programme (Mental Hub iCBT for Depression) to evaluate whether or not this treatment can reduce the number of sickness absence days in public sector employees aged 18-34 years who present at the occupational health service with mild depressive symptoms (score ≥9 on the Beck Depression Inventory-IA). Control participants will be offered CAU, with no constraints regarding the range of treatments. The active condition will consist of seven weekly modules of iCBT, with support from a web therapist. Primary outcome will be participants' all-cause sickness absence as indicated in employer's and national administrative records up to 6 months from study entry. Secondary outcomes relating to long-term sickness absence (over 11 calendar days) for mental and musculoskeletal disorders and psychotropic medication use will be obtained from the Finnish Social Insurance Institution's administrative records; and short sickness absence spells (up to 11 calendar days) will be extracted from employer's records. Analyses will be conducted on an intention-to-treat basis. ETHICS AND DISSEMINATION: The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa has approved the study (HUS/974/2019). The results will be published in peer-reviewed scientific journals and in publications for lay audience. TRIAL REGISTRATION NUMBER: ISRCTN10877837.

Reducing health inequalities trough digital options in mental health: A physician's perspective.

This article explores the physicians' perspective regarding the potential of computerized cognitive behavioral therapies (cCBTs) to overcome inequalities in the context of mental health care provision. The main benefits were related to the ability of cCBTs to provide care in a convenient and efficient manner, enhancing its accessibility. These aspects were perceived more important than cost-effectivity of treatment, which is often claimed to be the key benefit of cCBTs. Age and general acceptance of CBT were the most significant individual-level separators of perceptions, while the sector in which the physician works was seen as the main structural-level separator.

Therapeutic alliance in guided internet therapy programs for depression and anxiety disorders - A systematic review.

OBJECTIVE: The role of internet therapy programs for mental disorders is growing. Those programs employing human support yield better outcomes than do those with no such support. Therapeutic alliance may be a critical element in this support. Currently, the significance of therapeutic alliance in guided, internet-delivered cognitive behavioral therapy programs (iCBT) remains unknown. This review aims to determine whether the therapeutic alliance influences outcome of iCBTs and if it does, what plausible factors underlie this association. METHOD: Towards that goal searches were made in PubMed, PsycINFO, SCOPUS, The Cochrane Library and CINAHL in May 2016 and January 2017. RESULTS: From the 1658 relevant studies, only six studied the relationship of therapeutic alliance and outcome. All six studies showed a high level of client-therapist alliance; in the three most recent studies, the alliance was directly associated with outcome. No studies reported alliance-adherence associations. CONCLUSIONS: Alliance research in iCBT for mental disorders is scarce. Therapeutic alliance seems to associate with outcomes. More studies are necessary to define the optimal support to strengthen alliance. iCBT is a feasible environment for alliance research both practically and theoretically. The impact of alliance on adherence to iCBT requires study.

Should patients with schizophrenia receive antidepressants?

Antipsychotics play a key role in the pharmacological treatment of schizophrenia, and monotherapy is effective for most patients. Achieving an optimal treatment response is, however, often difficult. Combining an antidepressant drug to the antipsychotic regimen could potentially improve treatment outcomes, although the evidence supporting the use of such combinations is limited and contradictory. Positive evidence has mostly been obtained from the efficacy of antidepressants acting on monoamine receptors on the negative symptoms of schizophrenia. These receptor-active drugs may also improve cognition in schizophrenic patients. In the light of current knowledge, antidepressants do not appear to potentiate the psychotic symptoms of schizophrenic patients. However, there is no robust evidence of the efficacy of antidepressants in the treatment of schizophrenia-related depression, and thus monotherapy with an antipsychotic drug is recommended for treating it. If using antidepressants in addition to antipsychotics is deemed necessary, the risk of pharmacodynamic and pharmacokinetic interactions should be kept in mind.

Add-on mirtazapine improves orgasmic functioning in patients with schizophrenia treated with first-generation antipsychotics.

AIM: Sexual dysfunction, common in schizophrenia, may be further exaggerated by antipsychotics, especially those of First Generation (FGAs), and antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRs). Mirtazapine, an antidepressant characterized by its different action mechanism compared with that of the majority of other antidepressants, may improve SSRI-induced sexual dysfunction in patients with depression. It is unknown, however, whether mirtazapine improves sexual functioning in schizophrenia. METHODS: This study randomly assigned FGA-treated patients with schizophrenia to receive either an add-on mirtazapine (n = 20) or a placebo (n = 19) for 6 weeks. Sexual functioning was prospectively measured using five relevant items from the Udvalg for Kliniske Undersogelser side-effect rating scale (UKU-SERS). RESULTS: Orgasmic function improved with statistical significance in the mirtazapine group (p = .03), with no changes in any other sexual functions in either group. CONCLUSION: Add-on mirtazapine appears to relieve orgasmic dysfunction in FGA-treated patients with schizophrenia.

Is there an interrelationship between the effects of antipsychotics on psychopathology and on metabolism?

BACKGROUND: Increased body weight and hyperlipidemia caused by antipsychotics may be associated with improved antipsychotic efficacy in schizophrenia. If this association has a causal interrelationship via a genuine pathophysiological mechanism, then body weight loss in antipsychotic-treated patients would be accompanied by worsened psychopathology. This could have clinical implications. AIM: To explore whether the decreased body weight in these patients is associated with a worsened psychopathology. METHODS: In our previously published study, a 16 week treatment period with add-on orlistat (but not placebo) resulted in body weight loss in male (but not female) clozapine- or olanzapine-treated overweight or obese patients. In the current study, we investigated whether body weight loss in those male patients could worsen psychosis. Changes in the Positive and Negative Syndrome Scale (PANSS) scores within groups and body weight changes and lipid profiles over the treatment period were analysed by the paired samples t-test. Between-group comparisons were analysed by the independent samples t-test. RESULTS: Over the treatment period body weight decreased by 2.56 ± 3.25 kg from initial 106.02 ± 12.61 kg (p = 0.04) for the orlistat group, with no statistically significant changes for the placebo group. Lipid levels did not change in either group. The orlistat-induced weight decrease was not associated with worsening in the PANSS scores. CONCLUSIONS: Weight loss was not associated with a worsening of psychosis. The interrelationship between the antipsychotic-induced weigh gain and improved schizophrenia psychopathology observed in earlier studies appears to be indirect. Orlistat treatment in our study did not worsen psychopathology in this population.

[Online therapies - what is known about their functionality]. / Nettiterapiat - mitä tiedetään toimivuudesta.

Online therapies are partly automated therapies, in which psychotherapeutic contents have been complemented with computer-aided presentational and educational contents, with a therapist giving support to the progress of the patient. As methods, these therapeutic programs incorporate therapeutic methods that have proven effective, such as remodeling of thoughts, activation of behavior and exposure, empathy, strengthening of cooperative relationship and motivation, and general support for self-reflection. For instance, online therapies already constitute part of the Finnish treatment guidelines on depression. Online therapies are available throughout Finland for the essential psychiatric illnesses.

[Update on Current Care Guideline: Borderline personality disorder]. / Epävakaa persoonallisuus.

Borderline personality disorder is a severe disorder that increases disability to a considerable extent. Emotional instability, difficulties in regulating behavior and interpersonal relationships are essential features of the disorder. Borderline personality disorder has a more favorable course than previously thought. Dialectic behavioral therapy, cognitive therapy, mentalization therapy and transference-focused psychotherapy seem to be effective. Hospital treatment should be carried out primarily in day hospital settings. Antipsychotics and mood stabilizers may be used for a range of symptoms. SSRIs may be useful in the treatment of impulsivity and aggression. Benzodiazepines should be avoided.

Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia.

BACKGROUND: Despite adequate treatment with antipsychotics, a substantial number of patients with schizophrenia demonstrate only suboptimal clinical outcome. To overcome this challenge, various psychopharmacological combination strategies have been used, including antidepressants added to antipsychotics. METHODS: To analyze the efficacy of add-on antidepressants for the treatment of negative, positive, cognitive, depressive, and antipsychotic-induced extrapyramidal symptoms in schizophrenia, published randomized controlled trials assessing the efficacy of adjunctive antidepressants in schizophrenia were reviewed using the following parameters: baseline clinical characteristics and number of patients, their on-going antipsychotic treatment, dosage of the add-on antidepressants, duration of the trial, efficacy measures, and outcomes. RESULTS: There were 36 randomized controlled trials reported in 41 journal publications (n=1582). The antidepressants used were the selective serotonin reuptake inhibitors, duloxetine, imipramine, mianserin, mirtazapine, nefazodone, reboxetin, trazodone, and bupropion. Mirtazapine and mianserin showed somewhat consistent efficacy for negative symptoms and both seemed to enhance neurocognition. Trazodone and nefazodone appeared to improve the antipsychotics-induced extrapyramidal symptoms. Imipramine and duloxetine tended to improve depressive symptoms. No clear evidence supporting selective serotonin reuptake inhibitors' efficacy on any clinical domain of schizophrenia was found. Add-on antidepressants did not worsen psychosis. CONCLUSIONS: Despite a substantial number of randomized controlled trials, the overall efficacy of add-on antidepressants in schizophrenia remains uncertain mainly due to methodological issues. Some differences in efficacy on several schizophrenia domains seem, however, to exist and to vary by the antidepressant subgroups--plausibly due to differences in the mechanisms of action. Antidepressants may not worsen the course of psychosis. Better designed, larger, and longer randomized controlled trials are needed.

Association between Neurocognitive Impairment and the Short Allele of the 5-HTT Promoter Polymorphism in Depression: A Pilot Study.

Depression has been shown to be associated with cognitive deficits in various cognitive domains. However, it is still unclear which factors contribute to cognitive impairment. The objective of this study was to find out whether a functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene is associated with the impairment of cognitive functioning among depressed patients. In a pilot study, a sample of 19 patients with major depressive disorder (MDD) and 19 healthy controls was investigated with an extensive psychiatric and neuropsychological examination. All participants were genotyped for 5-HTTLPR. Depressed patients with the short allele of the 5-HTT promoter region exhibited inferior cognitive performance compared to patients with the long allele polymorphism. In healthy controls, no association between genotype and cognitive performance was found. The result suggests that in MDD patients with the short allele of the 5-HTTLPR polymorphism the vulnerability to cognitive impairment is increased compared to MDD patients without the short allele inheritance. These preliminary findings need to be confirmed in a larger cohort of MDD patients.

Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia--a path model investigation.

We aimed to evaluate predictors and mediators of enhancing effect of adjunctive mirtazapine on cognition in schizophrenia. Patients with difficult-to-treat schizophrenia received either mirtazapine (n = 19) or placebo (n = 18) in a double-blind fashion for six weeks. Mirtazapine outperformed placebo on the Block Design and Stroop Dots. In the present subsidiary study, factors underlying this difference were explored with Path Analysis. Add-on mirtazapine had an independent enhancing effect on the Block Design-measured visuo-spatial functioning. Further, this effect was mediated via changes in positive, depressive and parkinsonism symptoms, but not in negative symptoms. This effect was predicted by higher doses of FGAs, longer duration of illness and lower initial Block Design scores. Path Analysis model fit was good. Mirtazapine may have direct and indirect favorable effects on visuo-spatial functioning, but further research is needed. Path analysis may be a feasible statistical method for further research of neurocognition in psychopharmacological interventions in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

In a randomized placebo-controlled add-on study orlistat significantly reduced clozapine-induced constipation.

Constipation is a common and potentially fatal side effect of clozapine treatment. Another important side effect of clozapine may also be significant weight gain. Orlistat is a weight-control medication that is known to induce loose stools as a common side effect. This study aimed to explore whether orlistat used to control clozapine-induced weight gain can simultaneously tackle clozapine-related constipation. In this 16-week randomized-controlled study, clozapine-treated patients received add-on orlistat (n=30) or add-on placebo (n=24). Colonic function was measured using the Bristol Stool Form Scale. There was a significant (P=0.039) difference in the prevalence of constipation in favor of orlistat over placebo in completers (n=40) at the endpoint. A decrease in the prevalence of constipation within the orlistat group (P=0.035) was observed (vs. no statistically significant changes in the placebo group). In clozapine-treated patients, orlistat may be beneficial not only for weight control but also as a laxative. As no established treatments for clozapine-induced constipation exist, orlistat can be considered for this population, although more studies are required.