GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.
ISSUE 2, May 2012 — Guest Commentator: Sanjay Gupta, MD, S.U.N.Y., Buffalo, NY
Cassano GB, Rucci P, Benvenuti A, et al J Clin Psychiatry. 2012;73(1):22-28.
Objective: Multiple studies indicate that bipolar disorders are often underrecognized, misdiagnosed, and incorrectly treated. The aim of the present report is to determine which combination of clinical, demographic, and psychopathological factors and corresponding cutoff scores best discriminate patients with unipolar disorder from those with bipolar disorders.
Method: The study sample includes outpatients and inpatients (N = 1,158) participating in 5 studies carried out in the United States and Italy between October 2001 and March 2008, one of which was a randomized clinical trial. Diagnostic assessment was carried out with the SCID, which allows diagnoses to be made according to DSM-IV-TR criteria. Using an exploratory statistical approach based on a classification tree, we employed 5 mania spectrum factors and 6 depression spectrum factors derived from the Mood Spectrum Self-Report Instrument (MOODS-SR) in combination with demographic and clinical characteristics to discriminate participants with unipolar versus bipolar disorders.
Results: The psychomotor activation factor, assessing the presence of thought acceleration, distractibility, hyperactivity, and restlessness for 1 or more periods of at least 3 to 5 days in the lifetime, identified subgroups with an increasing likelihood of bipolar disorder diagnosis. Mixed instability and suicidality contributed to further subtyping the sample into mutually exclusive groups, characterized by a different likelihood of receiving a diagnosis of bipolar disorder. Of the demographic and clinical characteristics included in the analysis, only sex proved to be useful to improve the discrimination.
Conclusions: The psychomotor activation factor proved to be the most potent discriminator of those with unipolar versus bipolar diagnoses. The items that constitute this factor, together with those that constitute the mixed instability, suicidality, and euphoria factors, might be useful in making the differential diagnosis.
Clinical Commentary Bipolar disorder is often considered the “missed diagnosis” because patients tend to present during the depressed phase of the illness when manic symptoms are not obvious. Resulting prescription of antidepressants may cause the bipolar illness to accelerate. Thus, it is extremely important to discriminate between unipolar and bipolar depression as treatments differ. The items listed in the psychomotor activation factor facilitate this process as in the study and are also part of the 13-item Mood Disorder Questionnaire, which is a helpful clinical tool for this differentiation.
Banasr M, Dwyer JM, Duman RS Curr Opin Cell Biol. 2011;23(6):730-737. Epub 2011 Oct 11.
Depression is associated with structural alterations in limbic brain regions that control emotion and mood. Studies of chronic stress in animal models and postmortem tissue from depressed subjects demonstrate that these structural alterations result from atrophy and loss of neurons and glial cells. These findings indicate that depression and stress-related mood disorders can be considered mild neurodegenerative disorders. Importantly, there is evidence that these structural alterations can be blocked or even reversed by elimination of stress and by antidepressant treatments. A major focus of current investigations is to characterize the molecular signaling pathways and factors that underlie these effects of stress, depression, and antidepressant treatment. Recent advances in this research area are discussed and potential novel targets for antidepressant development are highlighted.
Clinical Commentary This study affirms that stress has an impact on brain structure over time, resulting in atrophy and loss of neurons and glial cells through various complex mechanisms. This article provocatively suggests that mood disorder may be a mildly degenerative problem. Eliminating stress may reverse the changes. Clinicians should realize the importance of a holistic approach in the management of a patient with major depression, which includes pharmacotherapy and psychotherapy as well as lifestyle changes to reduce stress and overall improvement of the individual patient. The relationships between continued stress, brain derived neurotrophic factor, cell loss, and cognitive impairment are complex and are becoming better understood.
Woerner MG, Correll CU, Alvir JM, et al Neuropsychopharmacology. 2011;36(8):1738-1746. Epub 2011 Apr 20.
Objective: Tardive dyskinesia (TD) rates with second-generation antipsychotics (SGAs) are considered to be low relative to first-generation antipsychotics (FGAs), even in the particularly vulnerable elderly population. However, risk estimates are unavailable for patients naïve to FGAs. Therefore, we aimed to determine the TD incidence in particularly vulnerable, antipsychotic-naïve elderly patients treated with the SGA risperidone or olanzapine.
Method: The present work describes a prospective inception cohort study of antipsychotic-naïve elderly patients aged >55 years identified at New York Metropolitan area in-patient and out-patient geriatric psychiatry facilities and nursing homes at the time of risperidone or olanzapine initiation. At baseline, 4 weeks, and at quarterly periods, patients underwent assessments of medical and medication history, abnormal involuntary movements, and extra-pyramidal signs. TD was classified using Schooler-Kane criteria. Included in the analyses were 207 subjects (age: 79.8 years, 70.0% female, 86.5% White), predominantly diagnosed with dementia (58.9%) or a major mood disorder (30.9%), although the principal treatment target was psychosis (78.7%), with (59.4%) or without (19.3%) agitation.
Results: With risperidone (n=159) the cumulative TD rate was 5.3% (95% confidence interval (CI): 0.7, 9.9%) after 1 year (mean dose: 1.0±0.76 mg/day) and 7.2% (CI: 1.4, 12.9%) after 2 years. With olanzapine (n=48) the cumulative TD rate was 6.7% (CI: 0, 15.6%) after 1 year (mean dose: 4.3±1.9 mg/day) and 11.1% (CI: 0, 23.1%) after 2 years. TD risk was higher in females, African Americans, and patients without past antidepressant treatment or with FGA co-treatment.
Conclusions: The TD rates for geriatric patients treated with risperidone and olanzapine were comparable and substantially lower than previously reported for similar patients in direct observation studies using FGAs. This information is relevant for all patients receiving antipsychotics, not just the especially sensitive elderly.
Clinical Commentary Clinicians may have become complacent about monitoring for tardive dyskinesia (TD) in antipsychotic-exposed patients, partly due to the widespread use of second-generation antipsychotics. Despite much lower risk of TD than with first-generation agents (SGAs), it is still necessary to monitor elderly patients for early signs of TD every 3 months using the Abnormal Involuntary Movement Scale (AIMS), as indicated in the study. The risk may be higher in females and African Americans. Despite the fact that SGAs risperidone and olanzapine are commonly used in the elderly when an antipsychotic is indicated, judicious use is indicated due to boxed warnings, especially when used off-label for dementia-related psychosis.
Martinez JM, Garakani A, Yehuda R, Gorman JM Depress Anxiety. 2012;29(1):32-8. Epub 2011 Sep 2
Objective: A number of studies have shown that elevated levels of inflammatory cytokines may promote depression and suicidal ideation and that neuroprotective peptides may decrease the response to stress and depression. In this study, cerebrospinal fluid (CSF) levels of three inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor α (TNFα)) and two putative "resiliency" neuropeptides (brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY)) were compared between patients with depression and healthy controls
Method: Eighteen patients with major depression and 25 healthy controls underwent a lumbar puncture; CSF samples were withdrawn and assayed for IL-1, IL-6, TNFα, BDNF, and NPY levels. Patients with depression were then entered into an 8-week treatment protocol and had repeated lumbar puncture procedures post-treatment.
Results: Contrary to prediction, we found that at baseline depressed patients had higher CSF NPY concentration compared to the normal comparison group. Within the depressed patients, we found several statistically significant correlations between elevated CSF cytokine levels and clinical severity.
Conclusions: Despite the small sample size, given the challenges in obtaining CSF from patients with depression these data are of interest in confirming some aspects of the inflammatory hypothesis of depression.
Clinical Commentary There continues to be a quest for biomarkers of depression akin to blood sugar in diabetes. This study conducted cerebrospinal fluid (CSF) measurements of various cytokines, brain derived neurotrophic factor (BDNF), and neuropeptide Y. Some of the findings, such as those related to BDNF and neuropeptide Y, were not expected, while there was good replication of cytokine elevation in the CSF in this disease state. In addition, the study suggests that high levels of TNF-alpha predicts poorer response to medication. Currently, this research suggests that some robust biomarkers for antidepressant response are being replicated while others are not. While this finding does not yet have much clinical implication, it is a research finding that clinicians should be aware of. More widespread use of these tests is currently limited by their invasive nature and a simpler way of measuring cytokines in the blood/CSF is warranted.
Molendijk ML, Bus BA, Spinhoven P, et al Mol Psychiatry. 2011 Nov;16(11):1088-1095. Epub 2010 Sep 21.
Objective: Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally.
Method: We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (≥6 months) and 382 healthy controls.
Results: We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St John's wort (P=0.03).
Conclusions: Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.
Clinical Commentary Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is linked to the viability of neurons in brain circuits regulating emotion. It is akin to “fertilizer for the brain.” The study’s findings, revealing that BDNF levels were low in patients with major depressive disorder, are of significance. BDNF may be an important biomarker for depression—a finding that needs to be further explored. In addition, the study found that depressed patients in remission and off antidepressant therapy had levels similar to normal controls. In comparison, there were lower levels in depressed patients who were not on antidepressant therapy, suggesting that normalization of BDNF levels may indicate remission. This also establishes low levels of BDNF as a state characteristic of depression. The BDNF levels were low in the early phase of remission, suggesting it may take time to normalize as other brain changes occur. Interestingly, the increase in serum levels of BDNF was specific to SSRIs and St. John’s wort. It is unclear why SSRIs and St. John’s wort (efficacy trials for major depression were negative) specifically increase BDNF levels. Clinicians should take into account that these are early biomarkers and continue to follow the research. Currently, data do not suggest that BDNF be measured in day-to-day clinical practice. SSRIs remain the first-line treatment for depression. St. John’s Wort still cannot be recommended as it is not FDA approved and does not have good supportive clinical trials and standardized production as a medication.
Huybrechts KF, Gerhard T, Crystal S, et al. BMJ. 2012;344:e977.
Objective: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.
Method: Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality. Participants: 75 445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65, were eligible for Medicaid, and lived in a nursing home in 2001-5. Main outcome measures Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.
Results: Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.
Conclusions: Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.
Clinical Commentary This study involved a large sample of residents in skilled nursing facilities (SNF) who were typical of patients treated by physicians in this type of setting. Atypical antipsychotics should be preferred in the SNF setting due to the lower risk of movement disorders, especially tardive dyskinesia, compared to the conventional antipsychotics. In an area where the usage of atypical antipsychotics is mostly off-label, risperidone has the advantage of being the best studied. However, this study suggests that quetiapine may be safer, although the efficacy of this agent is not as good as risperidone. Of note, the haloperidol group in the study had more preexisting cardiovascular problems and other comorbid conditions which should be taken into account. In rare instances where rapid control of an agitated patient is needed, haloperidol intramuscular (IM) may be used, though lorazepam IM can be tried first. There is also a separate body of literature attesting to the safety of haloperidol IV in high dosages given to delirious patients, though they were typically not SNF patients. In a compromised population, antipsychotics should be used judiciously, and the utilization and documentation of informed consent from healthcare proxies is important. The discussion should weigh in on a risk-benefit analysis, including the boxed warnings, and specific target symptoms for which the treatment is aimed should be clearly stated. Clinicians should be aware that the maximum dosages for these agents is much lower in the SNF population; for example, 2 mg for risperidone and 200 mg for quetiapine in divided doses. The most data for use is with risperidone, olanzapine, and quetiapine, respectively. Several studies suggest a higher risk of mortality in patients given haloperidol and lower risk in patients prescribed quetiapine. There is a likelihood that these effects are dose related. Data for divalproex are very limited. Also note that prescribing antidepressants as an alternative for dementia-related psychosis will not be helpful. In addition, periodic gradual dosage reduction (GDR) should be tried after a 3–4 month period of stabilization. If GDR fails, then documentation to that effect needs to be done by a psychiatrist, preferably a geriatric psychiatrist, and the patient should be continued on the medication. It is important to keep the family informed of the clinical situation.
Prakash Masand, M.D., is Senior Vice President and Chief Medical Officer, Neuroscience, for Clinical Care Options, which acquired Global Medical Education (GME) in 2020, a company Dr. Masand founded and where he served as CEO for 10 years. He is also the Co-Founder and CEO of Centers of Psychiatric Excellence (COPE). Dr Masand also serves as an Adjunct Professor with the Academic Medicine Education Institute at Duke-NUS
GME Research Review
GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.
ISSUE 1, April 2012 — Guest Commentator: Prakash Masand, MD, Global Medical Education, Inc.
Objective: The authors conducted a multisite randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease.
Method: Patients with schizophrenia or schizoaffective disorder with a body mass index ≥27 and non-high-density lipoprotein (non-HDL) cholesterol ≥130 mg/dl who were on a stable treatment dosage of olanzapine, quetiapine, or risperidone were randomly assigned to switch to aripiprazole (N=109) for 24 weeks or stay on their current medication (N=106). All participants were enrolled in a behaviorally oriented diet and exercise program. Clinical raters were blinded to treatment assignment. The primary and key secondary outcomes were change in non-HDL cholesterol and efficacy failure, respectively.
Results: The pre-specified primary analysis included 89 switchers and 98 stayers who had at least one post-baseline non-HDL cholesterol measurement. The least squares mean estimates of non-HDL cholesterol decreased more for the switch group than for the stay group (-20.2 mg/dl and -10.8 mg/dl, respectively). Switching was associated with larger weight reductions (least squares mean=2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two switchers (20.6%) and 18 stayers (17.0%) experienced protocol-defined efficacy failure. Forty-seven switchers (43.9%) and 26 stayers (24.5%) discontinued the assigned antipsychotic medication before 24 weeks.
Conclusions: Switching to aripiprazole led to improvement of non-HDL cholesterol levels and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy.
All atypical antipsychotics can be associated with weight gain and other metabolic problems that increase the risk for cardiovascular disease in psychiatric patients. However as the CATIE trial and other large studies have shown there is a differential risk of metabolic side effects with atypical antipsychotics. Olanzapine, clozapine and quetiapine have the greatest risk, asenapine, risperidone and iloperidone have an intermediate risk whereas ziprasidone, aripiprazole and lurasidone have the lowest risk. Hence, it is not surprising that patients with metabolic side effects on olanzapine, quetiapine and risperidone who were switched to aripiprazole had a decrease in weight and non-HDL cholesterol. However patients who were switched also had higher rates of discontinuation than stayers making the evaluation of the risk benefit ratio of switching extremely important and discussing it with the patient and their family before switching. Antipsychotics are not interchangeable in terms of efficacy as clinicians are often led to believe making relapse and functional worsening due to switching particularly at important lifepoints for patients potentially hazardous. Clinicians should monitor patients being switched closely for even minimal worsening of symptoms so appropriate actions including increasing dose of new antipsychotic, augmentation or switch to an alternate agent can be considered.
Context: Major depressive disorder, the most common psychiatric illness, is often chronic and a major cause of disability. Many patients with major depressive episodes who have an underlying but unrecognized bipolar disorder receive pharmacologic treatment with ineffective regimens that do not include mood stabilizers.
Objective: To determine the frequency of bipolar disorder symptoms in patients seeking treatment for a major depressive episode.
Design: Multicenter, multinational, transcultural, cross-sectional, diagnostic study. The study arose from the initiative Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE).
Setting: Community and hospital psychiatry departments.
Patients: Participants included 5635 adults with an ongoing major depressive episode.
Main Outcome Measures: The frequency of bipolar disorder was determined by applying both DSM-IV-TR criteria and previously described bipolarity specifier criteria. Variables associated with bipolarity were assessed using logistic regression.
Results: A total of 903 patients fulfilled DSM-IV-TR criteria for bipolar disorder (16.0%; 95% confidence interval, 15.1%-17.0%), whereas 2647 (47.0%; 95% confidence interval, 45.7%-48.3%) met the bipolarity specifier criteria. Using both definitions, significant associations (odds ratio > 2; P < .001) with bipolarity were observed for family history of mania/hypomania and multiple past mood episodes. The bipolarity specifier additionally identified significant associations for manic/hypomanic states during antidepressant therapy, current mixed mood symptoms, and comorbid substance use disorder.
Conclusions: The bipolar-specifier criteria in comparison with DSM-IV-TR criteria were valid and identified an additional 31% of patients with major depressive episodes who scored positive on the bipolarity criteria. Family history, illness course, and clinical status, in addition to DSM-IV-TR criteria, may provide useful information for physicians when assessing evidence of bipolarity in patients with major depressive episodes. Such an assessment is recommended before deciding on treatment.
Several studies have demonstrated that bipolar disorder is under-diagnosed and that bipolar patients see an average of 3 physicians and spend 10 years before receiving the correct diagnosis (Lish J 1994, Hirschfield et al. 2003). This study offers us what I often refer to as the “red flags” for bipolar disorder including family history of bipolar illness, multiple episodes of depression (usually at least three), hypomania in response to antidepressants, co-morbid substance use disorder and mixed mood symptoms. Other studies have found adolescent onset of depression, seasonal affective disorder, post partum depression and early and non sustained response to antidepressants as other red flags. Clinicians should look for these red flags in all patients presenting with depressive symptoms. In addition a corroborative history from family members is very valuable in picking up on a bipolar diagnosis since hypomania is an ego-syntonic state.
Background: Metabolic and cardiovascular health problems have become a major focus for clinical care and research in schizophrenia.
Aims: To evaluate the content and quality of screening guidelines for cardiovascular risk in schizophrenia.
Method: Systematic review and quality assessment of guidelines/recommendations for cardiovascular risk in people with schizophrenia published between 2000 and 2010, using the Appraisal of Guidelines for Research and Evaluation (AGREE).
Results: The AGREE domain scores varied between the 18 identified guidelines. Most guidelines scored best on the domains 'scope and purpose' and 'clarity of presentation'. The domain 'rigour of development' was problematic in most guidelines, and the domains 'stakeholder involvement' and 'editorial independence' scored the lowest. The following measurements were recommended (in order of frequency): fasting glucose, body mass index, fasting triglycerides, fasting cholesterol, waist, high-density lipoprotein/low-density lipoprotein, blood pressure and symptoms of diabetes. In terms of interventions, most guidelines recommended advice on physical activity, diet, psychoeducation of the patient, treatment of lipid abnormalities, treatment of diabetes, referral for advice and treatment, psychoeducation of the family and smoking cessation advice. Compared across all domains and content, four European guidelines could be recommended.
Conclusions: Four of the evaluated guidelines are of good quality and should guide clinicians' screening and monitoring practices. Future guideline development could be improved by increasing its rigour and assuring user and patient involvement.
Psychiatric patients have high rates of cardiometabolic disturbances (between 16.7%- 67%), often even prior to treatment. In addition atypical antipsychotics (particularly olanzapine, clozapine, quetiapine and to a lesser extent the others) can cause or worsen cardiometabolic conditions. Clinicians infrequently screen for cardiometabolic risk factors in psychiatric patients despite several guidelines as outlined in this paper. In one study the rate of screening at baseline in the APA/ADA pre-guideline and post-guideline cohorts was 8.4% and 10.5% respectively. At 12 weeks the rates of screening were 6.8% and 9.0% respectively (Haupt et al. 2009). Future efforts should focus on improving the extremely low rates of screening in psychiatric patients rather than the criteria for screening.
Objective: In clinical practice, antipsychotic drugs are widely used in borderline personality disorder (BPD). To evaluate current pharmacological treatment algorithms and guidelines for BPD, the authors reviewed and meta-analyzed studies on the effectiveness of antipsychotics on specific symptom domains in BPD.
Methods: The literature was searched for placebo-controlled, randomized clinical trials (PC-RCTs) on the effectiveness of antipsychotics regarding cognitive perceptual symptoms, impulsive behavioral dyscontrol, and affective dysregulation (with subdomains depressed mood, anxiety, anger, and mood lability) in BPD. Studies whose primary emphasis was on the treatment of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizotypal personality disorder or Axis I disorders were excluded.
Results: Meta-analyses were conducted using 11 retrieved studies including 1152 borderline patients. Antipsychotics have a significant effect on cognitive perceptual symptoms (9 PC-RCTs; standardized mean difference [SMD], 0.23) and mood lability (5 PC-RCTs; SMD, 0.20) as well as on global functioning (8 PC-RCTs; SMD, 0.25), but these effects have to be qualified as small. Antipsychotics have a more pronounced effect on anger (9 PC-RCTs; SMD, 0.39). Antipsychotics did not have a significant effect on impulsive behavioral dyscontrol, depressed mood, and anxiety in BPD.
Conclusion: Drug therapy tailored to well-defined symptom domains can have beneficial effects in BPD. At short term, antipsychotics can have significant effects on cognitive-perceptual symptoms, anger, and mood lability, but the wide and long-term use of antipsychotics in these patients remains controversial. The findings from this study raise questions on current pharmacological algorithms and clinical guidelines.
The effect sizes of the antipsychotics were small. Lamotrigine and topiramate have larger effect sizes in BPD. Studies have also not found any superiority of atypical antipsychotics to conventional neuroleptics or to each other. Pharmacotherapy plays a small but important role in the management of patients with BPD. It may be particularly helpful to make patients better candidates for therapies that are efficacious in this population
Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative) / Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window.
With the conventional neuroleptics clinicians often used the “ neuroleptic threshold dose, “(McEvoy et al. 1991) to determine optimum dosing for treating psychosis. With the atypical antipsychotics by definition efficacy occurs at doses that do not cause EPS. However the present analysis argues for a dose range to achieve efficacy based on occupancy of D2 receptors on PET scans (60%-78%) even among the atypical antipsychotics. This may explain the clinical observation that some patients with schizophrenia need doses at the higher end of the dose range and others at the lower end. This may also account for the observed efficacy of combining low doses of two atypical antipsychotics that clinicians often use in their practice.
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