Risperidone Augmentation Research Articles

Risperidone and fluvoxamine; two directions of augmentation: a case report

IntroductionOnly 40%–70% of patients have an adequate response to the first-line treatment of OCD with SSRIs. Antipsychotic augmentation is effective in the management of both obsessions and compulsions and these drugs are currently the first-line pharmacological augmenting agents for OCD. (Jaisoorya T, Thamby A. Antipsychotic augmentation in the treatment of obsessive-compulsive disorder. Indian Journal of Psychiatry. 2019;61(7):51)ObjectivesWe present the cases of a 31-year-old man and a 21- year-old girl. A 31 -year old man experienced hygienic obsessive and compulsive symptoms with excessive showering for one year (YBCOS 20). First, he was treated with 100 mg of fluvoxamine daily which helped him gain partial remission of symptoms. After a stressful period at work and his showering compulsions got worse. Our female patient suffered from compulsive hand washing and disinfection with fear of getting contaminated by other people (YBCOS 24). She was also treated for anorexia nervosa. At the moment of referral to our outpatient clinic, she had already been taking 2 mg of risperidone daily, but still, her compulsions persisted.MethodsBoth patients were included in outpatient service treatment. They were followed up weekly, psychotherapeutically supported and their psychopharmacotherapy was titrated. In the case of our male patient, risperidone of 1 mg/day was added to the ongoing fluvoxamine of 100 mg/day. Our female patient was given fluvoxamine 50 mg/a day and gradually increased to 100 mg/day with an ongoing 2 mg/day of risperidone.ResultsAfter two weeks, the hygiene compulsions of the 31-year-old-man completely remitted (YBCOS 6). He stopped excessive showering and became fully functional at work and in family relations. Our female patient also continued to take risperidone in augmentation with fluvoxamine as recommended. Her compulsions improved, and she returned to her hobbies and her college lectures (YBCOS 8). They have both been advised to continue outpatient psychiatric treatment and to regularly use pharmacotherapy.ConclusionsThe condition of both of our patients improved after adding an augmentative agent to the therapy. In the first case, it was risperidone as a fluvoxamine augmentation, and in the second, fluvoxamine was added as a risperidone augmentation. The combination of these two drugs, rather than each other being used on its own, proved to be a powerful therapeutic tool in the treatment of OCD. Further clinical studies are required for a better understanding of the underlying neurobiological mechanism of this effective combination.Disclosure of InterestNone Declared

The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.

Evaluation of the Effect of Fluvoxamine in Patients With Schizophrenia Under Risperidone Treatment: A Clinical Trial.

The effectiveness of selective-serotonin reuptake inhibitors in the improvement of schizophrenia is a controversial issue. The aim of this study was to evaluate the effect of fluvoxamine on the symptoms of schizophrenia including positive and negative symptoms, cognitive impairment, and quality of life. This clinical trial was performed on 68 patients with chronic schizophrenia, treated with risperidone at 22 Bahman Hospital of Qazvin, Iran during 2015 to 2016. The patients were randomly divided into control and intervention groups (34 patients per group). The control group was treated with risperidone and biperiden, whereas the intervention group received fluvoxamine, besides risperidone, and biperiden. The participants completed the Wechsler Memory Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms (SANS), and the World Health Organization Quality of Life Scale, and the findings were statistically analyzed at baseline and postintervention (8 and 10 weeks). The mean ± SD Wechsler Memory Scale scores in the evaluated intervals (baseline, week 8, and week 10), respectively, were 70.58 ± 11.51, 70.76 ± 11.36, and 70.88 ± 11.40 in the control group and 74.76 ± 10.56, 77.76 ± 10.56, and 77.76 ± 10.73 in the intervention group (F = 126.73, P ≤ 0.001). The difference between the groups in terms of SANS and quality of life scores was significant in the specified intervals, SANS (F = 6.36, P = 0.004), and quality of life (F = 15.13, P ≤ 0.001). Nevertheless, no difference was observed in terms of Scale for the Assessment of Positive Symptoms scores (P > 0.05). The results indicated that risperidone augmentation with fluvoxamine could significantly improve cognitive impairments and negative symptoms among patients with schizophrenia. Moreover, this augmentation led to higher quality of life among these patients.

EFFECTIVENESS OF RISPERIDONE AUGMENTATION IN OBSESSIVE-COMPULSIVE DISORDER – EXPERIENCE OF A SPECIALTY CLINIC IN INDIA

Background Randomized placebo-controlled trials suggest that risperidone may be efficacious as an add-on treatment to serotonin reuptake inhibitors (SRIs) in patients with obsessive compulsive disorder (OCD). Inherent limitations of these studies are the relatively small sample sizes and concern over their generalizability to real-world clinical practice. Also, factors predicting response to risperidone augmentation are unclear. Aim To assess the effectiveness of risperidone augmentation in OCD, and to study the predictors of response, in a real-world setting. Method 1314 consecutive patients who consulted a specialty OCD clinic between 2004 and 2014 at a large psychiatric hospital in India were evaluated with Mini International Neuropsychiatric Interview, the Yale-Brown Obsessive–Compulsive Scale, and the Clinical Global Impression scale. Patients with OCD initiated on risperidone, not having psychosis or mental retardation, without ongoing cognitive behavior therapy and who were on stable SRI medication for at least 12 preceding weeks were included for analysis. Primary outcome measure was all-cause discontinuation. Principal component analysis with Varimax rotation was conducted utilizing responses from YBOCS checklist, which yielded a 5-factor solution with the following dimensions - ‘pathological doubts/checking’, ‘need for symmetry/orderliness’, ‘forbidden thoughts’, ‘cleaning/contamination’, and ‘hoarding’. Predictors of treatment response were evaluated by logistic regression analysis (backward wald) with symptom dimensions and other relevant antecedent variables as independent variables and all-cause discontinuation as the dependent variable. Results 104 patients were eligible for analysis. In all except 24 patients (23.08%), risperidone had been discontinued at the time of last follow-up, either due to ineffectiveness or intolerability. 26 patients (25%) were noted to have at least 25 % reduction on YBOCS. 24 patients (23.08%) were marked either as ‘much improved’ or ‘very much improved’ on CGI-I. Mean reduction in YBOCS scores for the whole sample (n=104) was 13.54% (t=5.45, p On regression analysis, ‘forbidden thoughts’ predicted discontinuation of risperidone (p=0.021). Conclusions Risperidone proved to be an effective augmenting agent in a significant sub-set of patients with OCD. The drug may be less beneficial in patients with ‘forbidden thoughts’ (sexual, religious, or aggressive obsessions).

Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis

Objective: Major depressive disorder (MDD) affects about 10–15% of the general population in a lifetime. A considerable number of patients fail to achieve full symptom remission despite adequate treatment and are considered treatment resistant (TRD). The current study compared the relative efficacy and tolerability of pharmacological and somatic TRD interventions by means of a Bayesian network meta-analysis.Research design and methods: An electronic literature search of MEDLINE, MEDLINE In-Process, EMBASE, PsycInfo, EconLit and Cochrane Library databases for trials published between September 2003 and September 2014 was conducted. Key outcomes extracted were disease severity change from baseline, response and remission rates at various timepoints and discontinuation due to adverse events.Results: Of the 3876 abstracts identified, 31 publications/randomised controlled trials (RCTs) were included in the analysis; 19 RCTs investigating 13 pharmacological interventions and 12 RCTs investigating electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). The evidence synthesis investigating efficacy outcomes of TRD treatments demonstrated superior efficacy for ketamine compared to pharmacological and somatic interventions at 2 weeks after treatment initiation. At 4, 6 and 8 weeks, quetiapine augmentation (800 mg/day) and risperidone augmentation were found to be the first and second best treatments, respectively. Networks were small for response rate and remission rate outcomes at most timepoints. The most tolerable treatment was lamotrigine augmentation showing a comparable profile to placebo/sham.Conclusions: This analysis revealed scarcity of long-term data on sustained remission that would allow a comparative long-term efficacy assessment. Key limitations of the analysis can be considered the search timeframe and the use of mapping formula for the depression scores.

Effectiveness of Risperidone Augmentation in Obsessive-Compulsive Disorder: Experience From a Specialty Clinic in India.

Risperidone is the most widely used augmenting agent in the treatment of obsessive-compulsive disorder (OCD). However, a recent controlled study found risperidone to be no different from placebo, raising doubts about its effectiveness. In this context, we sought to examine the real-world effectiveness of risperidone from the large database of an OCD clinic in India. A total of 1314 consecutive patients who registered at the OCD clinic between 2004 and 2014 were evaluated with structured interviews and scales. Patients with OCD initiated on risperidone augmentation without concurrent cognitive behavior therapy and who were on stable and adequate doses of serotonin reuptake inhibitors for at least 12 preceding weeks were included for analysis. The primary outcome measure was all-cause discontinuation. Logistic regression was performed to identify the factors predicting improvement with risperidone augmentation. A total of 92 patients were eligible for analysis. Risperidone continued to be used in 23 patients (25%) at the time of last follow-up, and the remaining discontinued either because of ineffectiveness or intolerability. The fall in the Yale-Brown Obsessive-Compulsive Scale scores was significantly greater in patients who continued to take risperidone when compared with those who did not (41.6% vs 3.7%, t = 6.95, P < 0.001). A total of 22 patients (24%) were noted to have at least a 25% reduction on the Yale-Brown Obsessive-Compulsive Scale scores. On regression analysis, no predictors of improvement with risperidone augmentation could be identified. The study demonstrated, in a real-world setting, that risperidone may be a useful augmenting agent in a proportion of patients with partial/poor response to serotonin reuptake inhibitors.

Evaluation of the Efficacy of Antipsychotic Drugs in Sri-resistant Obsessive-compulsive Disorder

Background In a previous meta-analysis investigating pharmacological treatment options in obsessive-compulsive disorder (OCD) we determined a significant efficacy for the augmentation of serotonin reuptake inhibitors (SRIs) with antipsychotic drugs. Because new relevant double-blind, randomized, placebo-controlled trials (DB-RCTs) evaluating new antipsychotics were conducted, we updated our meta-analysis. Methods We included all DB-RCTs that compared augmentation of SRIs with antipsychotics to placebo augmentation in SRI-resistant OCD. Meta-analytic outcomes were treatment response defined by 35% reduction in Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) total score and mean changes in Y-BOCS total score. Effect sizes were standardized mean differences (SMD) and risk ratios (RR). Results Fourteen DB-RCTs (n=467) investigating quetiapine (N=5, n=178), risperidone (N=3, n=72), aripiprazole (N=2, n=79),olanzapine (N=2, n=70), haloperidol (N=1, n=34), and paliperidone (N=1, n=34) were incorporated. The pooled antipsychotic augmentation group was significantly superior to the placebo group in terms of response rates (N=14,n=467; RR=1.98, 95% CI: 1.23 to 3.19;p=0.005) and mean change in Y-BOCS total score (N=14, n=465, SMD=-0.6, 95% CI: -0.97 to -0.23; p=0.002). Concerning the individual antipsychotics, aripiprazole and risperidone significantly outperformed placebo in terms of both responder rates and mean Y-BOCS change. Olanzapine, paliperidone, and quetiapine were not significantly different from the control group. There was no significant heterogeneity and no evidence for publication bias. Conclusions Aripiprazole and risperidone augmentation of SRIs canbe regarded as evidence-based treatment options in treatment-resistant OCD and showed superiority over olanzapine, paliperidone, and quetiapine. About one third of all SRI-resistant OCD subjects responded to augmentation with antipsychotic drugs.

The Ritual of Hyperbaric Oxygen and Lessons for the Treatment of Persistent Postconcussion Symptoms in Military Personnel

During the past decade, unprecedented clinical and research resources have been directed toward addressing 2 conditions considered “silent” and “signature injuries” of the Iraq and Afghanistan wars, namely, posttraumatic stress disorder (PTSD) and concussion (m i l d t r auma t i c b r a i n injury). This investment is increasingly paying dividends in knowledge and interventions that are changing the standards of clinical practice. Notable examples include emerging trauma-focused psychotherapies and the antihypertensive prazosin hydrochloride for PTSD.1 However, along with these successes have also come seemingly promising interventions that in due course are shown to lack efficacy when tested in clinical trials such as the multicenter trial of risperidone augmentation for PTSD.1 This issue of JAMA Internal Medicine publishes results of a clinical trial that illuminates the challenges in designing effective interventions for silentwar-related injuries.2While the sample size was modest, this unique well-designed 3-arm double-blindstudyofhyperbaricoxygen (HBO) treatmentprovides compelling results with broad implications. Seventytwo service members who experienced concussions (including at least 1 concussion during war-zone deployment) and werehavingpersistentpostconcussionsymptoms (≥4months’ duration) were randomized to receive 40 HBO treatments (100%oxygenat1.5atmospheresabsolute for60minutes5days per week), a sham procedure (40 equivalent sessions involving slightly pressurized room air, sufficient to induce a feeling of inner ear pressure), or routine postconcussion care. Results showed that both the HBO and sham procedures were associated with significant improvements in postconcussion symptoms and secondary outcomes, including PTSD (which most participants had), depression, sleep quality, satisfactionwith life, andphysical, cognitive, andmental health functioning. However, there were no significant differences betweenHBOand the shamprocedure, and change scores for all secondary outcomes favored sham. Although this trialwas technically apilot investigationdesigned to produce data necessary for a pivotal study and will not likely end debate on this topic (given tenacious advocacy byHBOproponents3), these results are consistentwith 2other sham-controlledclinical trialsamongservicemembersandveterans involving a range ofHBOdoses.2 Given the outstanding methods, consistency in results, and lack of dose response across thesestudies, it is increasinglyhard toargue thataphase 3 trial of HBO for the treatment of postconcussion symptoms (or PTSD) is warranted. This conclusion is disappointing for servicemembers and veterans experiencing war-related symptoms but offers important lessons and anopportunity to engage in reneweddialogue concerning the priorities for future interventions. This dialogue requires us to begin by acknowledging that no new treatments for persistent blast or impact–related postconcussion symptomshavebeen identified, despite the extensive investment to date. The evidence remains weak and inconsistent for both pharmacological (eg, stimulant or cholinergic augmentation) and nonpharmacological (eg, cognitive rehabilitation) interventions.4,5 The only evidence-based treatment shown to be effective in attenuating persistent symptoms after concussion, based on clinical trials in civilian populations, is cognitive education to promote expectations of recovery.4,5However,despite thisbeingemphasizedasacornerstone of treatment guidelines,4 research is lacking to replicate or refine educational interventions in military or veteranpopulations.Furthermore, concernshavebeenraised that current screening approaches, combined with a specialtydriven structure of concussion care in the Veterans Health Administration and Department of Defense, may inadvertently promote negative, rather than positive, recovery expectations.5,6 ThisHBOclinical trial highlights a principal barrier to successful concussion-related interventions,namely, the fact that the condition of persistent postconcussion symptoms is such an elusive target for treatment that effective interventions will likely not be identified until this condition is reconceptualized.4-6 Postconcussion symptoms typically involve headaches, fatigue, cognitive and memory problems, sleep disturbance, irritability, dizziness and balance problems, andothers.However, these symptoms areubiquitous in general medical practice, they are associated with numerous different conditions, and no validated clinical case definition exists, oneofmany reasonswhy thisHBOpilot studywas conducted. Multiple studies amongmilitary and veteran populationshave shown thatpersistent cognitive andphysical symptoms attributed to concussion in the postdeployment period are much more likely to be associated with conditions other than concussion, including PTSD, depression, grief, nonconcussive injuries, or associated comorbidities (eg, chronic pain andsleepdysfunction).5-7Underlyingneuroendocrineandautonomic nervous system dysregulation likely mediates these multisymptom trauma-spectrum responses.1,5 Two-thirdsof servicemembers in thisHBOstudyhadadiagnosis ofPTSD (basedonstructuredclinical interviews), 44% were taking daily pain medication, and the mean depression scores were in the depressed range (with more than half takRelated article page 43 Hyperbaric Oxygen in Postconcussion Service Members Original Investigation Research

Effectiveness of aripiprazole, olanzapine, quetiapine, and risperidone augmentation treatment for major depressive disorder: a nationwide population-based study.

Previous studies suggested that antidepressants augmented with second-generation antipsychotics (SGAs), including aripiprazole, olanzapine, quetiapine, and risperidone, resulted in better treatment response or higher rates of remission in patients with major depressive disorder (MDD). However, population-based study on SGA augmentation for patients with MDD remains limited. The purpose of this study was to investigate the effectiveness of SGA augmentation for treatment of MDD using the National Health Insurance Research Database in Taiwan. The subjects were patients with MDD (ICD-9-CM code: 296.2 and 296.3) who were initially admitted to psychiatric inpatient settings for the first time between January 1, 1996, and December 31, 2007, and could be tracked until December 31, 2011. To assess the treatment effect of SGA augmentation, 993 MDD patients who received aripiprazole, olanzapine, quetiapine, or risperidone augmentation treatment for 8 weeks or more were included in this 1-year mirror-image study. Outcome measures included length of psychiatric hospitalization and number of psychiatric admissions and emergency room (ER) visits. After patients received SGA augmentation treatment, key psychiatric service use (including length of psychiatric hospitalization [P < .0001], number of psychiatric admissions [P < .0001], and ER visits [P = .0006]) due to MDD diagnosis was significantly reduced. Subgrouping analysis for each SGA drug also showed significant reduction in number of psychiatric admissions for MDD patients who received aripiprazole (P < .0001), olanzapine (P = .003), quetiapine (P < .0001), and risperidone (P < .0001). The study provides support that aripiprazole, olanzapine, quetiapine, and risperidone augmentation therapy could be effective in reducing psychiatric service utilization among MDD patients.

Impact of self-reported juvenile abuse on treatment outcome in patients with major depressive disorder

BackgroundWe assessed the impact of juvenile abuse (emotional, physical, or sexual) on response to treatment in adults with major depressive disorder (MDD) suboptimally responsive to antidepressant therapy. MethodsA post hoc analysis explored the relationship between self-reported history of juvenile abuse and response to risperidone or placebo augmentation during a 6-week double-blind study period in patients with MDD suboptimally responsive to a previous adequate trial of antidepressant monotherapy. ResultsOverall, only one clinical measure showed a small, but statistically significant difference in outcome between patients with abuse versus without abuse (HRSD-17). In patients reporting abuse (n=141), improvement with risperidone versus placebo augmentation was greater on several measures: HRSD-17 total and 2 subscale scores, responder rates, Q-LES-Q, and PaRTS-D. In patients without abuse (n=127), only two measures showed significant improvement: HRSD-17 subscale and PaRTS-D. Responder rates (HRSD-17) were: 40.9% (risperidone) versus 23.1% (placebo; p=0.01; odds ratio=2.7) in those with abuse, and 41.0% versus 34.4% (p=0.39; odds ratio=1.4) in those without. Adverse events rates were: 37.0% (risperidone) and 54.4% (placebo) in patients with abuse, and 56.3% and 55.6% in those without. LimitationsAnalysis not preplanned. Validated questionnaire not used to determine abuse status. ConclusionsSelf-reported juvenile abuse history may impact response to risperidone augmentation therapy in adults with MDD suboptimally responsive to antidepressants. Abuse status may reduce placebo response and reporting of adverse events.

Prevalence of Depression in Patients With Chest Pain and Non-Obstructive Coronary Artery Disease

Many studies have demonstrated the prevalence of depression in patients with coronary artery disease (CAD), but few have examined this relation in those with chest pain who do not have obstructive CAD on angiography. The aim of this study was to compare the prevalence of depression amongst patients with chest pain in the presence or absence of obstructive CAD and a healthy control group without chest pain. This prospectively designed, observational cohort study used 2 independent data sets: (1) The Queen Elizabeth Hospital Coronary Angiogram Database (n = 1,144), consisting of 819 patients with obstructive CAD and 325 patients with nonobstructive CAD (NoCAD), all of whom had chest pain and (2) the North West Adelaide Health Study (NWAHS; n = 3,168), a population-based biomedical cohort, from which patients with chest pain were excluded. The presence of depression was determined by a previously validated method using the Short Form 36. The prevalence of depression differed among the 3 groups, with 63% in those with NoCAD, 53% in those with CAD, and only 24% in the healthy NWAHS cohort. Analysis of the angiography cohort revealed age, gender, antidepressant medication, previous myocardial infarction, previous airway disease, Short Form 36 physical summary score, Seattle Angina Questionnaire physical limitation score, and NoCAD on angiography to be independent predictors of depression. In conclusion, these findings highlight the importance of screening for depression in patients with NoCAD.

Risperidone augmentation with amisulpride: The blue‐tongue sign

Risperidone augmentation with amisulpride: The blue‐tongue sign

Dopamine Pharmacological Agents in Resistant-OCD

The paper provides a brief summary of current preclinical and clinical evidences of dopaminergic system involvement in OCD pathophysiology. We also provide an overview of effectiveness and long-term safety of dopaminergic agents in the treatment of resistant OCD. Keywords: OCD, resistant-OCD, antipsychotics augmentation, dopamine agents, ondansetron, endogenous, placebo-controlled, quetiapine, olanzapine, aripiprazole, Haloperidol, risperidone augmentation, Sydenham's chorea, amphetamine, cocaine

Efficacy and safety of treatments for refractory generalized anxiety disorder

This study systematically collated clinical evidence on refractory generalized anxiety disorder (GAD). Refractory GAD patients are those who have failed to respond adequately to at least one earlier treatment for GAD. MEDLINE, EMBASE, The Cochrane Library and conference proceedings were searched to identify trials. Four placebo-controlled trials (pregabalin, olanzapine, quetiapine, risperidone) and four single-arm studies (aripiprazole, risperidone, quetiapine, ziprasidone) evaluated the add-ons to initial treatment(s) or switch of treatment(s) because of inadequate efficacy. The most robust trial was the pregabalin study, with a study duration of 8 weeks and a largest sample size that consists of 356 patients. A significant reduction in the Hamilton Anxiety Scale (HAM-A) score was found for pregabalin and risperidone augmentation compared with placebo. Olanzapine augmentation resulted in a significantly higher proportion of responders (using HAM-A scores) compared with placebo. Quetiapine augmentation did not result in significantly greater mean reductions in the HAM-Ascores compared with placebo. There is a need for effective and safe augmentation treatments for patient's refractory to initial treatments for GAD. This study has located one large robust trial assessing the add-on to pregabalin. All other trials were small and unpowered studies with less than 50 patients. Further high-quality trials of augmentation treatment on refractory GAD are required.

The comparison of aripiprazole and risperidone augmentation in selective serotonin reuptake inhibitor‐refractory obsessive‐compulsive disorder: a single‐blind, randomised study

To investigate the comparative efficacy of aripiprazole and risperidone as augmenting agents in the treatment of obsessive-compulsive disorder (OCD) patients who did not show a ≥35% decrease in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) after 12-week monotherapy with selective serotonin reuptake inhibitors (SSRIs). The study consists of two different periods of treatment: a 12-week prospective period to determine resistance to SSRI treatment and an 8-week single-blind addition period for refractory patients only. Ninety patients were randomly assigned to receive one of the SSRI treatments. Sixty-nine patients (76.6%) completed the 12-week SSRI monotherapy period. Forty-one patients (59.4%) were considered refractory and were randomised to receive either risperidone (20 patients, 3 mgr daily) or aripiprazole (21 patients, 15 mgr daily) as augmentation to SSRI treatment. Sixteen patients (76.2%) in the aripiprazole group and 18 patients (84%) in the risperidone group completed the 8-week treatment period. Eight patients (50%) in aripiprazole and 13 patients (72.2%) in risperidone group met response criteria of Y-BOCS decrease ≥35% at the end of the study. The risperidone group showed a significant improvement in Y-BOCS obsession scores compared with aripiprazole. The present findings suggest that risperidone may be more effective than aripiprazole.

Use of Risperidone as Augmentation Treatment for Major Depressive Disorder

To review the efficacy and safety of risperidone for augmentation treatment in patients with major depressive disorder who fail to achieve adequate response to antidepressant monotherapy. A search of MEDLINE (1966-August 2010) and EMBASE (1980-August 2010) was conducted, using the terms risperidone and major depressive disorder. In addition, a manual search of the references cited in each publication identified from the database search was conducted to identify relevant articles. All English-language, peer-reviewed publications identified from the data sources were evaluated. Four clinical trials and 1 subanalysis of a clinical trial were included for analysis. Risperidone is an atypical antipsychotic that displays antidepressant properties due to its activity at various serotonergic and dopaminergic receptors. Studies have demonstrated that risperidone augmentation may be effective and safe when used at low doses. Although several of the studies identified had limited sample sizes, all studies demonstrated improvement on various standardized depressive symptom assessment scales. Study durations ranged from 4 to 24 weeks, with doses ranging from 0.25 to 2 mg/day. The most common adverse effects associated with risperidone therapy were headache, dry mouth, and increased appetite. Clinical evidence suggests that the use of risperidone as adjunctive therapy for treatment-resistant depression may improve rates of response and remission, but long-term effectiveness and safety cannot be determined at this time. Therefore, an adequate trial of first-line agents from different classes and/or a combination of agents from different classes would be recommended prior to initiation of risperidone. If the decision is made to start risperidone, health-care providers should ensure that patients are educated regarding the potential benefits and adverse effects before initiating risperidone.

Second-generation antipsychotics for major depressive disorder and dysthymia

Major depressive disorder (MDD) is a common condition with a lifetime prevalence of 15% to 18%, which leads to considerable suffering and disability. Some antipsychotics have been reported to induce remission in major depression, when added to an antidepressant. To evaluate the effects of second-generation antipsychotic (SGA) drugs (alone or augmentation) compared with placebo or antidepressants for people with MDD or dysthymia. The Cochrane Depression, Anxiety and Neurosis Group's controlled trial registers (CCDANCTR-Studies and CCDANCTR-References) were searched up to 21 July 2010. The author team ran complementary searches on clinicaltrials.gov and contacted key authors and drug companies. We included all randomised, double-blind trials comparing oral SGA treatment (alone or augmentation) with other forms of pharmaceutical treatment or placebo in people with MDD or dysthymia. We extracted data independently. For dichotomous data we calculated the odds ratio (OR) and 95% confidence interval (CI) on an intention-to-treat basis, and for continuous data the mean difference (MD), based on a random-effects model. We presented each comparison separately; we did not perform a pooled data analysis. We included 28 trials with 8487 participants on five SGAs: amisulpride, aripiprazole, olanzapine, quetiapine and risperidone.Three studies (1092 participants) provided data on aripiprazole augmentation in MDD. All efficacy data (response n = 1092, three RCTs, OR 0.48; 95% CI 0.37 to 0.63), (MADRS n = 1077, three RCTs, MD -3.04; 95% CI -4.09 to -2) indicated a benefit for aripiprazole but more side effects (weight gain, EPS) .Seven trials (1754 participants) reported data on olanzapine. Compared to placebo fewer people discontinued treatment due to inefficacy; compared to antidepressants there were no efficacy differences, olanzapine augmentation showed symptom reduction (MADRS n = 808, five RCTs, MD -2.84; 95% CI -5.48 to -0.20), but also more weight or prolactin increase.Quetiapine data are based on seven trials (3414 participants). Compared to placebo, quetiapine monotherapy (response n = 1342, three RCTs, OR 0.52; 95% CI 0.41 to 0.66) and quetiapine augmentation (response n = 937, two RCTs, OR 0.68; 95% CI 0.52 to 0.90) showed symptom reduction, but quetiapine induced more sedation.Four trials (637 participants) presented data on risperidone augmentation, response data were better for risperidone (n = 371, two RCTs, OR 0.57; 95% CI 0.36 to 0.89) but augmentation showed more prolactin increase and weight gain.Five studies (1313 participants) presented data on amisulpride treatment for dysthymia. There were some beneficial effects compared to placebo or antidepressantsbut tolerability was worse. Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.

Psychometric evaluation of a Patient-Rated Most Troubling Symptom Scale for Depression: findings from a secondary analysis of a clinical trial

The objective of this study was to assess the reliability and validity of the presence and severity of eight symptoms rated on the Patient-Rated Troubling Symptoms for Depression (PaRTS-D) instrument used in a risperidone augmentation trial. PaRTS-D total score (sum of four most severe symptoms) and global total score (sum of all eight symptoms) were determined weekly. Clinician-rated and patient-rated instruments were completed at selected time points. Statistical tests of reliability and validity were performed. The frequency of symptoms rated as one of the four most troubling were sadness, 73.5%; trouble concentrating, 70.9%; reduced involvement, 61.9%; tense/uptight, 56.0%; reduced sleep, 52.2%; negative thoughts, 42.9%; inability to feel emotion, 26.5%; and reduced appetite, 13.1%. Evidence of two factors (somatic-related and depression-related) was observed in the exploratory factor analysis. Baseline PaRTS-D total score correlated with the Quality of Life Enjoyment and Satisfaction Questionnaire and the Sheehan Disability Scale. PaRTS-D global total score showed high internal consistency reliability. PaRTS-D total score and global total score distinguished between patients with high and low-Hamilton Rating Scale for Depression Scores and were responsive to Patient Global Improvement Scale changes. The PaRTS-D total score minimal important difference was 4-5 points. In conclusion, PaRTS-D may be useful in symptom presence and severity assessments from the patient's perspective and as an adjunctive to other instruments in major depressive disorder diagnosis and response to treatment.

Drs. Nelson and Papakostas Reply

Drs. Nelson and Papakostas Reply

The combined use of risperidone long-acting injection and clozapine in patients with schizophrenia non-adherent to clozapine: a case series

Poor adherence to clozapine treatment represents an important problem in clinical practice because additional useful treatment options are unavailable. Although switching to risperidone long-acting injection (RLAI) has been recommended for those with compliance problems, this medication has been found to be less suitable for patients who previously received clozapine. Based on the suggested beneficial effects of RLAI, such as higher rates of treatment continuation and patient satisfaction, and the possible effectiveness of oral risperidone augmentation, it seems worthwhile to try RLAI augmentation for clozapine non-adherence. In this article, we present the cases of four patients with schizophrenia undergoing combined treatment with RLAI and clozapine for more than one year after multiple relapses related to clozapine non-adherence. Durations and frequencies of hospitalizations markedly declined after RLAI augmentation. Indeed, three patients receiving RLAI and clozapine for 1.2-3.5 years were never hospitalized during this period. The lengths of hospitalizations before and after augmenting with RLAI were 54.7 +/- 33.1 and 4.2 +/- 4.2 days/year, respectively. Participants also showed great improvements in social skills. These findings suggest the possible beneficial effects of RLAI augmentation in cases of clozapine nonadherence. However, controlled clinical trials are necessary to confirm whether RLAI augmentation represents a useful treatment option for patients who have not adhered to clozapine treatment.