Adjunctive Pharmacologic Treatment Research Articles

PXL01 alters macrophage response with no effect onaxonal outgrowth or Schwann cell response after nerve repair in rats.

Background: Adjunctive pharmacological treatment may improve nerve regeneration. We investigated nerve regeneration processes of PXL01- a lactoferrin-derived peptide - after repair of the sciatic nerve in healthy Wistar rats.Materials & methods: PXL01, sodium hyaluronate (carrier) or sodium chloride was administered around the repair. After 6days axonal outgrowth, Schwann cell response, pan- (CD68) and pro-healing (CD206) macrophages in sciatic nerve, sensory neuronal response in dorsal root ganglia (DRG) and expression of heat shock protein 27 (HSP27) in sciatic nerves and DRGs were analyzed.Results: Despite a lower number of pan-macrophages, other investigated variables in sciatic nerves or DRGs did not differ between the treatment groups.Conclusion: PLX01 applied locally inhibits inflammation through pan-macrophages in repaired sciatic nerves without any impact on nerve regeneration or pro-healing macrophages.

Cannabidiol, cognition and schizophrenia: a narrative review

Schizophrenia is a serious mental disorder affecting about 1% of the population. It is characterised by multiple symptoms which are mostly responsive to treatment with antipsychotic medications. Cognitive impairment is regarded as a core feature of illness which is mostly poorly responsive to treatment with the current antipsychotic medications. Improving cognitive function is an important treatment goal as it is associated with better outcomes in employment and quality of life. Adjunctive pharmacological treatments have been examined to improve measures of cognition but with limited success. Cannabidiol (CBD), has shown promise in preclinical models of cognitive deficits of schizophrenia. On the other hand, limited studies in small groups of patients with schizophrenia have shown no significant clinical benefits for cognitive function as an adjunct to ongoing treatment with antipsychotics. A single trial, in which CBD as a standalone treatment was compared to the antipsychotic medication amisulpride, showed significant changes in cognitive measures for both agents, with no statistically significant difference between them. It might therefore be concluded that the preclinical findings have failed to translate to the clinic. However, the preclinical findings themselves are based on a circumscribed set of studies in multiple cognitive models and have used varying doses and routes of drug administration. The same general methodological issues are present in the suite of clinical studies. Issues such as patient heterogeneity in terms of illness duration, formulation and dose of CBD employed, and length of cannabinoid treatment might militate positive findings. The limited clinical database available makes the benefits (or lack thereof) of CBD for the cognitive effects of schizophrenia uncertain. Continued research in much larger patient populations than have so far been investigated as well as a consideration of dose ranging studies are required to fully assess the potential risks against the benefits of CBD treatment for cognitive deficits in schizophrenia.

Patient journey in gastroesophageal reflux disease: real-world perspectives from Italian gastroenterologists, primary care physicians, and ENT specialists.

Gastroesophageal reflux disease (GERD) is a challenging condition that involves different physicians, such as general practitioners (GPs), gastroenterologists, and ears, nose and throat (ENT) specialists. A common approach consists of proton-pump inhibitors (PPIs) administration. Adjunctive pharmacological treatment may have a role in the management of non-responders to PPIs. We aimed to survey GPs and different medical specialists to investigate the medical approaches to patients reporting GERD symptoms. In addition, we examined the use of adjunctive pharmacological treatments in patients with GERD symptoms who do not respond to PPIs. Retrospective observational study. A survey was conducted among a large sample of gastroenterologists, GPs, and ENT specialists. Symptoms were divided into typical and extraesophageal, and their severity and impact on quality of life were explored with the GERD Impact Scale and with Reflux Symptom Index (RSI). All therapies administered usually for GERD were investigated. A total of 6211 patients were analyzed in this survey. Patients with typical symptoms were 53.5%, while those with extraesophageal symptoms were 46.5%. The latter were more frequently reported by ENT patients (53.6%, p < 0.0001). The GSI was higher in patients followed by gastroenterologists (9 points) and GPs (9 points) than ENT specialists (8 points), but the RSI was higher in the ENT group (14.3 ± 6.93) than in GPs and gastroenterologist groups (10.36 ± 6.36 and 10.81 ± 7.30, p < 0.0001). Chest pain had the highest negative impact on quality of life (p < 0.0001). Of the 3025 patients who used PPIs, non-responders showed a lower GSI when treated with a combination of adjunctive pharmacological treatments and bioadhesive compounds, than with single-component drugs. Patients with GERD referred to a gastroenterologist had more severe disease and poorer quality of life. The combination of adjunctive pharmacological treatments and bioadhesive compounds seems to be effective in the management of PPI refractory patients.

Effect of tramadol as an adjunctive pharmacological treatment for major depressive disorder: a randomised, double-blind, placebo-controlled trial

Effect of tramadol as an adjunctive pharmacological treatment for major depressive disorder: a randomised, double-blind, placebo-controlled trial

Deep Learning Analyses of Brain MRI to Identify Sustained Attention Deficit in Treated Obstructive Sleep Apnea: A Pilot Study.

Persistent sustained attention deficit (SAD) after continuous positive airway pressure (CPAP) treatment is a source of quality of life and occupational impairment in obstructive sleep apnea (OSA). However, persistent SAD is difficult to predict in patients initiated on CPAP treatment. We performed secondary analyses of brain magnetic resonance (MR) images in treated OSA participants, using deep learning, to predict SAD. 26 middle-aged men with CPAP use of more than 6 hours daily and MR imaging were included. SAD was defined by psychomotor vigilance task lapses of more than 2. 17 participants had SAD and 9 were without SAD. A Convolutional Neural Network (CNN) model was used for classifying the MR images into +SAD and -SAD categories. The CNN model achieved an accuracy of 97.02±0.80% in classifying MR images into +SAD and -SAD categories. Assuming a threshold of 90% probability for the MR image being correctly classified, the model provided a participant-level accuracy of 99.11±0.55% and a stable image level accuracy of 97.45±0.63%. Deep learning methods, such as the proposed CNN model, can accurately predict persistent SAD based on MR images. Further replication of these findings will allow early initiation of adjunctive pharmacologic treatment in high-risk patients, along with CPAP, to improve quality of life and occupational fitness. Future augmentation of this approach with explainable artificial intelligence methods may elucidate the neuroanatomical areas underlying persistent SAD to provide mechanistic insights and novel therapeutic targets.

Two clinical cases of adjunctive use of a SGLT-2 inhibitor in type 1 diabetes

Type 1 diabetes mellitus (T1DM) prevalence is increasing and despite all available modern treatment options, an overall small but noticeable increase of mean HbA1c was recently observed in various registries. Authorized adjunctive pharmacological treatment options to insulin therapy are still scarce for T1DM. In February 2019, the European Medicines Agency (EMA) approved dapagliflozin as first in class sodium/glucose co-transporter 2 inhibitor (SGLT-2i) adjunctive therapy to insulin in patients with T1DM, which is currently still not approved by the FDA in the United States. SGLT-2is have shown significant improvement in HbA1c, reducing body weight and increasing time-in-range by reducing glycaemic variability, as well as reductions in total daily insulin dose in the trials in persons with T1DM. The cases presented here translate some of the observations gained from clinical trials into a real-world environment. They demonstrate that even highly practised and educated patients can benefit from the addition of a SGLT-2i as adjunctive treatment to insulin in T1DM. In summary, these cases demonstrate that a variety of patients with T1DM in a real-world setting may benefit from SGLT-2i treatment, as they have the potential to improve HbA1c, excess of body weight and increasing TiR among other things.

The ESC ACCA EAPCI EORP acute coronary syndrome ST-elevation myocardial infarction registry.

The Acute Cardiac Care Association (ACCA)-European Association of Percutaneous Coronary Intervention (EAPCI) Registry on ST-elevation myocardial infarction (STEMI) of the EurObservational programme (EORP) of the European Society of Cardiology (ESC) registry aimed to determine the current state of the use of reperfusion therapy in ESC member and ESC affiliated countries and the adherence to ESC STEMI guidelines in patients with STEMI. Between 1 January 2015 and 31 March 2018, a total of 11462 patients admitted with an initial diagnosis of STEMI according to the 2012 ESC STEMI guidelines were enrolled. Individual patient data were collected across 196 centres and 29 countries. Among the centres, there were 136 percutaneous coronary intervention centres and 91 with cardiac surgery on-site. The majority of centres (129/196) were part of a STEMI network. The main objective of this study was to describe the demographic, clinical, and angiographic characteristics of patients with STEMI. Other objectives include to assess management patterns and in particular the current use of reperfusion therapies and to evaluate how recommendations of most recent STEMI European guidelines regarding reperfusion therapies and adjunctive pharmacological and non-pharmacological treatments are adopted in clinical practice and how their application can impact on patients' outcomes. Patients will be followed for 1 year after admission. The ESC ACCA-EAPCI EORP ACS STEMI registry is an international registry of care and outcomes of patients hospitalized with STEMI. It will provide insights into the contemporary patient profile, management patterns, and 1-year outcome of patients with STEMI.

Pregabalin as adjunctive therapy in benzodiazepine discontinuation.

The available evidence for the use of pregabalin as adjunctive therapy in the discontinuation of benzodiazepines is reviewed. Pregabalin has been studied as an adjunctive pharmacologic treatment for the discontinuation of long-term benzodiazepine use. Unlike carbamazepine, pregabalin has little potential for drug interactions, and its adverse effects are mostly mild and transient. Pregabalin reduces the release of excitatory neurotransmitters by binding to regulatory subunits of voltage-activated calcium channels. The majority of studies evaluated failed to find a significant difference in benzodiazepine discontinuation rates between pregabalin and comparator groups. The long-term efficacy of pregabalin in benzodiazepine discontinuation is also unknown, as patients were only followed for 0-12 weeks after discontinuing the benzodiazepines. Most studies, however, did observe consistent improvement in withdrawal symptoms, anxiety symptoms, and cognitive function with pregabalin use in benzodiazepine discontinuation. Studies varied in design elements, such as whether past benzodiazepine discontinuation attempts occurred, baseline benzodiazepine use characteristics (agent, dose, duration), benzodiazepine discontinuation strategies previously used, and the use of comorbid psychiatric diagnoses and concurrent psychotropics as exclusion criteria. In addition, the literature does not clearly describe whether patients successfully discontinued pregabalin, for which there are reports of substance abuse. Based on the current available evidence, pregabalin is not recommended for use in benzodiazepine discontinuation, as the majority of studies did not find a significant difference in benzodiazepine discontinuation rates between pregabalin and comparatory groups despite an improvement in withdrawal and anxiety symptoms.

Bleeding associated with the management of acute coronary syndromes

### Learning objectives Rupture or erosion of a coronary artery atheroma exposes flowing blood to the prothrombotic contents of the plaque, resulting in platelet activation and subsequent thrombus formation. If...

Loneliness

In 1978, when the Task Panel report to the U.S. President’s Commission on Mental Health emphasized the importance of improving health care and easing the pain of those suffering from emotional distress syndromes including loneliness, few anticipated that this issue would still need to be addressed 40 years later. In 2011, a meta-analysis on the efficacy of treatments to reduce loneliness identified a need for well-controlled randomized clinical trials focusing on the rehabilitation of maladaptive social cognition. We review assessments of loneliness and build on this meta-analysis to discuss the efficacy of various treatments for loneliness. With the advances made over the past 5 years in the identification of the psychobiological and pharmaceutical mechanisms associated with loneliness and maladaptive social cognition, there is increasing evidence for the potential efficacy of integrated interventions that combine (social) cognitive behavioral therapy with short-term adjunctive pharmacological treatments.

Pharmacotherapy of Co-Occurring Schizophrenia and Substance Use Disorders.

Substance use disorders, common in patients with schizophrenia, can lead to poor outcomes. Here we review the literature on the use of antipsychotics in patients with co-occurring schizophrenia and substance use disorder as well as evidence for the use of adjunctive pharmacological treatments targeting substance use in these patients. We also discuss a neurobiological formulation suggesting that the cooccurrence of these disorders may be related to a dysfunction in the dopamine mediated brain reward circuitry. Typical antipsychotics do not appear to decrease substance use in this population. Randomized, controlled trials provide some support for use of the atypical antipsychotic clozapine for co-occurring cannabis use disorder, naltrexone and disulfiram for alcohol use disorder, and also nicotine replacement therapy, sustained-release bupropion and varenicline for tobacco use disorder. Nonetheless, data regarding treatment in patients with these co-occurring disorders are still limited, and many studies reported to date have been either underpowered or did not include a control condition. Further research is needed to evaluate optimal pharmacotherapeutic strategies for this population.

Fatigue across the CNS spectrum: a clinical review

Fatigue is reflected in a broad array of symptoms that can be particularly impactful in patients with central nervous system (CNS) disorders. Fatigue symptoms can present as core components of the underlying CNS disorder, as part of co-morbid medical conditions, as secondary to psychosocial stressors or physical or mental exertion, and/or secondary to the medications used to treat the disorders. The complex, multi-factorial etiology of fatigue symptoms can obscure the assessment and complicate the treatment intervention for the underlying primary CNS disorder. In this narrative clinical review, we focus on identification, assessment, and adjunctive pharmacological treatment of fatigue symptoms across five distinct CNS disorders. Given the potential impact of fatigue on function and quality of life, it is important to address this symptom as part of a comprehensive evaluation.

Looking back into the future: desirudin in acute coronary syndromes and coronary stenting

Although percutaneous coronary intervention (PCI) is a highly effective modality for the management of acute coronary syndromes, it can potentiate the existing prothrombotic state around lesion areas and lead to ischaemic complications. Adjunctive pharmacologic treatment with heparin reduces the risk of ischaemic events, but the utility of heparin is limited by its unpredictable pharmacodynamic effects and its inability to modulate fibrin-bound thrombin. Additionally, a potential risk of heparin-induced thrombocytopenia is associated with heparin use. Direct thrombin inhibitors (DTIs) have emerged as potential alternatives to heparin in patients undergoing PCI. Bivalirudin is a DTI indicated for use in PCI. Results from various studies have suggested clinical benefit associated with the use of bivalirudin, driven primarily by the reduction in bleeding risks compared with the standard treatment regimens. Of concern, however, is a significant increase in acute stent thrombosis with bivalirudin monotherapy compared with heparin plus GPIIb/IIIa inhibitors following primary PCI for ST-segment elevation myocardial infarction (STEMI). Desirudin is a highly potent DTI with greater binding affinity than bivalirudin for thrombin. This report provides a comparative overview of the pharmacology and clinical utility of desirudin and bivalirudin in the setting of PCI.

Perfil da intervenção coronária percutânea no infarto agudo do miocárdio com supradesnivelamento do segmento ST no Brasil de 2006 a 2010: registro CENIC

INTRODUÇÃO: O infarto agudo do miocárdio (IAM) persiste como importante causa de morbidade e mortalidade. Este estudo visa a delinear o panorama nacional da intervenção coronária percutânea (ICP) no cenário do IAM, analisando diferentes períodos e regiões do Brasil, com enfoque na ICP primária e nos tratamentos adjuntos farmacológicos e mecânicos. MÉTODOS: Foram analisados dados de 20.004 pacientes com diagnóstico de IAM com supradesnivelamento do segmento ST (IAMCSST) e submetidos a ICP, provenientes do Registro CENIC (Central Nacional de Intervenções Cardiovasculares), de janeiro de 2006 a dezembro de 2010. Esses dados são oriundos de 252 centros localizados em 22 Estados das cinco regiões do País. RESULTADOS: A ICP primária correspondeu a 57,8% das ICPs realizadas no contexto do IAM, seguida de ICP eletiva pós-IAMCSST (35,7%), ICP de resgate (6,1%) e ICP facilitada (0,4%). A evolução ao longo dos anos evidencia aumento progressivo do número de ICPs primárias no Brasil, partindo de 56,7% do total em 2006 para 71,6% em 2010. O tempo médio porta-balão da ICP primária no Brasil nesse período foi de 2 horas. A aspiração de trombos aumentou de 0,4% em 2006 para 8,2% dos casos em 2010. A taxa média de sucesso do procedimento foi de 93,8%, enquanto a de óbito hospitalar foi de apenas 2,8%. CONCLUSÕES: A ICP no cenário do IAMCSST vem apresentando avanços de 2006 a 2010, embora de maneira heterogênea nas diferentes regiões do Brasil, mediante aumento das taxas de ICP primária e maior utilização de dispositivos de aspiração de trombo, os quais ainda não foram incorporados na rotina. Investimentos em recursos humanos e implementação de protocolos de atendimento constituem elementos essenciais para a otimização do tempo porta-balão e para a melhora dos resultados clínicos.

P03-108 - Adherence to antidepressant treatment in depressive patients with comorbid psychiatric disorders

BackgroundDepression is associated with high rates of comorbidity with other psychiatric disorders. Adherence to antidepressant medication regimens has been associated to different factors. Few studies have analyzed the influence of comorbid psychiatric disorders and adjunctive pharmacological treatments on antidepressant adherence.AimThe study evaluates the association of comorbid psychiatric disorder and pharmacological treatments with adherence rates to antidepressants in a large sample of depressive outpatients.Method3606 depressive patients were included in a cross-sectional epidemiological study, involving a stratified sample of 750 psychiatrists selected to participate. Patients were included if they met DSM-IV criteria for current single or recurrent non-psychotic major depressive disorder. Simplified Medication Adherence Questionnaire (SMAQ) and Hamilton Depression Rating Scale (HDRS) were used to assess adherence and depression severity.ResultsAdherence rates are lower in depressive patients with psychiatric comorbidity (62.8%) than in patients without comorbidity (69.1%) (Chi-square = 15.9, p &lt; 0.001, OR = 1.6, 1.2–1.8). There are no significant differences in adherence rates between those patients taking or not benzodiacepines.ConclusionsPsychiatric comorbidity plays a negative role in adherence to antidepressant treatment. Benzodiazepine use has no influence on adherence rates. Special attention should be paid to the symptom overlapping between anxiety and depression and to the benzodiazepine prescription in comorbid depressive patients.

Weight-Loss Programs in Convenient Care Clinics: A Prospective Cohort Study

Assess whether a convenient care clinic (CCC) medical weight-loss program can promote weight loss. Prospective cohort study with follow-up at 10 weeks. A CCC (Lindora Health Clinic) weight-loss program (Lean for Life) based in a retail pharmacy (Rite Aid Pharmacy) in Costa Mesa, California. The first 100 people to purchase the weight-loss program. A 10-week, $465 medical weight-loss program with individual counseling sessions; a hypocaloric diet of 900 to 1200 kcal/day (25%-30% carbohydrates, 40% protein, 25% fat); and adjunctive pharmacologic treatment, if necessary. We collected data on age, height, weight, visits per week, medication use, comorbid conditions, and weight change. Data were analyzed based on length of enrollment and mean percent weight loss. Statistical tests used were t-test and Spearman rank correlation test. Eighty-six subjects had valid data entries for weight change over the 10-week period. Average age was 51.6 years; mean starting body mass index was 30.3. Thirty patients participated for 0 to 4 weeks, 30 for 4 to 9 weeks, and 26 for 10 weeks. Mean percent weight changes for the 0 to 4, 5 to 9, and 10-week groups were -1.6, -6.0, and -8.1, respectively. Forty-five (45%) of the patients achieved medically significant weight loss (> or =5%). The study shows that a medical weight-loss program offered at a CCC in a retail pharmacy can produce medically significant weight loss of > or =5%. Further research of collaborations between the retail and medical weight-loss industries is warranted. Study design limitations included selection bias and confounding variables other than the weight-loss program.

Potential Limitations in Generalizing Findings From the TORDIA Study

Back to table of contents Previous article Next article Letters to the EditorFull AccessPotential Limitations in Generalizing Findings From the TORDIA StudySUSAN MOORE M.D.JOHN COONEY M.D.,SUSAN MOORE M.D.Search for more papers by this authorJOHN COONEY M.D.Search for more papers by this author,Published Online:1 Aug 2009https://doi.org/10.1176/appi.ajp.2009.09050639AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In the April 2009 issue of the Journal , David A. Brent, M.D., et al. (1) examined predictors of suicidal adverse events in the treatment of selective serotonin reuptake inhibitor (SSRI) resistant depression in adolescents. The authors found that adjunctive use of benzodiazepines in a small patient group (N=10 [3% of the total sample]) was associated with a higher rate of both suicidal and non-suicidal self-injury. They concluded that the disinhibitory effects of benzodiazepines may lead to increased risk-taking behavior. This finding was reiterated in an accompanying editorial (2) . We suggest that this finding in such a small subgroup more likely represents a selection bias. Patients with comorbid anxiety disorders who have a higher risk of suicidal behaviors (3) are more likely to require adjunctive pharmacological treatment. Benzodiazepines may also have been prescribed for high levels of distress or agitation in this subgroup, which would also lead to an increase in self-harming behaviors. Given the small sample size and lack of information about comorbid diagnoses, the authors’ conclusion cannot be generalized to the population as a whole. Dublin, IrelandDr. Cooney has served on the speaker’s bureau for Eli Lilly, GlaxoSmithKline, and Pfizer; and he has served on an advisory panel for Servier. Dr. Moore reports no competing interests.This letter (doi: 10.1176/appi.ajp.2009.09050639) was accepted for publication in June 2009.

Outcome after primary percutaneous intervention in acute myocardial infarction: role of microcirculatory perfusion--a crucial piece in the puzzle

ST elevation myocardial infarction (STEMI) constitutes ∼40% of all acute myocardial infarction (AMI), which continues to be a significant public health problem in both developed and developing counties.1,2 Primary percutaneous intervention (PCI) is now established as the reperfusion therapy of choice after STEMI. The aim of reperfusion therapy for many years has focused on achieving epicardial artery patency at the site of the occlusive thrombus. It is now possible, through advances in interventional techniques and adjunctive pharmacological treatment, to achieve TIMI (Thrombosis In Myocardial Infarction) grade 3 epicardial flow (normal) in ∼95% of patients. Despite this achievement, mortality, although declining, still remains high.3 This is possibly because, despite restoration of TIMI grade 3 flow, ∼40% of patients do not achieve microvascular flow, which should be the goal of reperfusion therapy.4 The no-reflow phenomenon (absence or reduced microvascular flow despite restoration of epicardial coronary artery patency) was first described by Kloner et al. 5 Electron microscopy showed microvascular obstruction due to endothelial blebbing, white cell infiltration, red call stagnation, and extracellular … *Corresponding author. Tel: +44 20 8869 2547/2548, Fax: +44 20 8864 0075, Email: roxysenior{at}cardiac-research.org

Pharmacological Prevention of Peri-, and Post-Procedural Myocardial Injury in Percutaneous Coronary Intervention

In recent years, percutaneous coronary intervention (PCI) has become a well-established technique for the treatment of coronary artery disease. PCI improves symptoms in patients with coronary artery disease and it has been increasing safety of procedures. However, peri- and post-procedural myocardial injury, including angiographical slow coronary flow, microvascular embolization, and elevated levels of cardiac enzyme, such as creatine kinase and troponin-T and -I, has also been reported even in elective cases. Furthermore, myocardial reperfusion injury at the beginning of myocardial reperfusion, which causes tissue damage and cardiac dysfunction, may occur in cases of acute coronary syndrome. Because patients with myocardial injury is related to larger myocardial infarction and have a worse long-term prognosis than those without myocardial injury, it is important to prevent myocardial injury during and/or after PCI in patients with coronary artery disease. To date, many studies have demonstrated that adjunctive pharmacological treatment suppresses myocardial injury and increases coronary blood flow during PCI procedures. In this review, we highlight the usefulness of pharmacological treatment in combination with PCI in attenuating myocardial injury in patients with coronary artery disease.

Adjunctive treatment of acute mania: a clinical overview

To provide an overview of the available high quality evidence-base of studies of adjunctive pharmacologic treatment for acute mania. Double-blind controlled trials with adequate samples (n > 100) were identified through search of PubMed/MEDLINE and computerized abstracts from 2004-2006 meetings of the American Psychiatric Association, International Conference on Bipolar Disorder, and Collegium Internationale Neuro-Psychopharmacolium using key words mania, adjunct, and combination. Placebo-controlled studies with positive results support the adjunctive use of five agents including valproate, olanzapine, risperidone, quetiapine, and haloperidol. Agents with only negative or failed placebo-controlled studies included carbamazepine, gabapentin, lamotrigine, topiramate, oxcarbazepine, and ziprasidone. We found no placebo-controlled study of many commonly used agents including lithium, aripiprazole, and clozapine. No studies explicitly excluded subjects, based on prior treatment with the monotherapy being offered and several studies limited randomization to patients with documented inadequate response to the monotherapy arm. The available placebo-controlled randomized clinical trials support adjunctive therapy combining lithium or valproate with olanzapine, risperidone, haloperidol or quetiapine. The additional increment of antimanic efficacy of these combinations over monotherapy was similar in magnitude to that seen for the same agents as monotherapy in comparison with placebo. These additive benefits enhanced the tolerability of adverse effects sufficiently to allow a higher proportion of subjects receiving combination therapies to complete the studies than monotherapy treated patients. The available data has several shortcomings and the available studies are inadequate to conclusively determine whether combination treatment is more efficacious than monotherapy when used by subjects naive to both treatments. Nevertheless, adjunctive treatment, which combines agents with proven antimanic efficacy, offers an attractive option for patients with acute mania.