Maintenance Treatment Of Bipolar Disorder Research Articles

What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium.

AimsTo systematically review the existing trials on optimal serum levels for lithium for maintenance treatment of bipolar disorder and to develop clinical recommendations.MethodsSystematic literature search. Discussion of major characteristics, limitations, methodological quality, and results of selected trials. Delphi survey consisting of clinical questions and corresponding statements. For statements endorsed by at least 80% of the members, consensus was considered as having been achieved.ResultsWith strict inclusion criteria no studies could be selected, making it difficult to formulate evidence‐based recommendations. After loosening the inclusion criteria 7 trials were selected addressing our aims at least to some extent. Four of these studies suggest better efficacy being associated with lithium serum levels in a range above a lower threshold around 0.45/0.60 and up to 0.80/1.00 mmol/L. These findings support the outcome of the Delphi survey.ConclusionsFor adults with bipolar disorder there was consensus that the standard lithium serum level should be 0.60‐0.80 mmol/L with the option to reduce it to 0.40‐0.60 mmol/L in case of good response but poor tolerance or to increase it to 0.80‐1.00 mmol/L in case of insufficient response and good tolerance. For children and adolescents there was no consensus, but the majority of the members endorsed the same recommendation. For the elderly there was also no consensus, but the majority of the members endorsed a more conservative approach: usually 0.40‐0.60 mmol/L, with the option to go to maximally 0.70 or 0.80 mmol/L at ages 65‐79 years, and to maximally 0.70 mmol/L over age 80 years.

Lithium for acute mania.

Lithium for acute mania.

Effects of GADL1 overexpression on cell migration and the associated morphological changes

Lithium has been used for maintenance treatment of bipolar disorder, but drug response varies among patients. Single-nucleotide polymorphisms in glutamate decarboxylase–like protein 1 (GADL1) are found to be associated with lithium response in Han Chinese bipolar patients. In this study, we assessed GADL1 function using a neuroblastoma cell line that stably overexpressed GADL1. Genes encoding factors involved in cell migration, such as FN1, ITGA2, ITGAV and CCL2, were downregulated in GADL1-overexpressing cells. GADL1 overexpression indeed suppressed cell migration. Cell migration speed and perimeter length exhibited similar trends, both of which were decreased under GADL1 overexpression or lithium treatment but increased upon stimulation with CCL2. Secreted GADL1 or its enzyme product, taurine, in the conditioned medium might exert only mild effects on the observed changes. Compared with SH-SY5Y cells, GADL1-overexpressing cells were much more sensitive to CCL2 treatment but less sensitive to lithium, indicating that the level of GADL1 expression can affect cell sensitivity to lithium or CCL2 treatment. Together, these results suggest that cell migration and related morphological changes might provide good indicators of the sensitivity toward lithium treatment, and the GADL1 stable overexpression cell line might serve as a useful platform to screen novel therapeutics for bipolar disorder.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patientdonors, we measured circadian rhythms in skinfibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Long-acting injectable antipsychotics as maintenance treatments for bipolar disorder-A critical review of the evidence.

The maintenance phase of bipolar disorder is arguably the most important. The aim of management during this time is to maintain wellness and prevent future episodes of illness. Medication is often the mainstay of treatment during this phase, but adherence to treatment is a significant problem. In recent years, long-acting injectable (LAI) solutions have been proposed, but these too have limitations. This paper discusses the options that are currently available and critically appraises the effectiveness of this strategy. The authors reviewed the small number of open-label and randomised studies on LAI medications in bipolar disorder and evaluated the efficacy and safety of these medications. The studies reviewed show benefit of LAIs for the management of bipolar disorder but have several key limitations to the generalisability of findings to routine practice. LAIs have an emerging role in the management of bipolar disorder and, although it is not without limitations, this strategy addresses some issues of long-term treatment and medication. Patients with bipolar disorder that are non-adherent or have an unstable illness with a predilection towards mania are possibly better suited to the use of LAIs, though more research is required to fully assess the effectiveness of this approach.

Challenging the Negative Perception of Lithium and Optimizing Its Long-Term Administration.

The use of lithium for the prevention of recurrences in mood disorders has a 55-year history. Nowadays, lithium is universally accepted as the first-choice mood-stabilizer (MS) for maintenance treatment of bipolar disorder. In addition to its mood-stabilizing properties, lithium exerts anti-suicidal, immunomodulatory and neuroprotective action which may further substantiate its clinical usefulness. Despite these facts, the use of lithium in mood disorders has been greatly underutilized. The reasons include the introduction and promoting other MS as well as a perception of lithium as a “toxic drug” due to its side effects, mainly thyroid, renal and cognitive disturbances. The trends in lithium prescription in recent decades show relative stability or a decline at the expense of other mood-stabilizing drugs, both first generation (valproate) and second generation (olanzapine, quetiapine, lamotrigine). In this review article, the negative perception of lithium by some clinicians will be challenged. First, the data showing lithium superiority over other MS will be presented. Second, the lithium-induced side effects which can make a challenge for a more frequent application of this drug will be delineated, and their proper management described. Finally, an issue of benefits of long-term administration of lithium will be discussed, including the phenomenon of the “excellent lithium responders” (ER) as well as a subject of starting lithium prophylaxis early in the course of the illness. This review article is based on the 47-year experience with lithium therapy by the author of the article.

Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms

BackgroundThe antiepileptic lamotrigine is approved for maintenance treatment of bipolar disorder and augmentation therapy in treatment-resistant depression. Previous preclinical investigations showed lamotrigine antidepressant-like effects without addressing its possible activity on motivational aspects of anhedonia, a symptom clinically associated with poor treatment response and with blunted mesolimbic dopaminergic responsiveness to salient stimuli in preclinical models. Thus, in rats expressing a depressive-like phenotype we studied whether repeated lamotrigine administration restored behavioral responses to aversive and positive stimuli and the dopaminergic response to sucrose in the nucleus accumbens shell (NAcS), all disrupted by stress exposure. MethodsDepressive-like phenotype was induced in non-food-deprived adult male Sprague-Dawley rats by exposure to a chronic protocol of alternating unavoidable tail-shocks or restraint periods. We examined whether lamotrigine administration (7.5 mg/kg twice a day, i.p.) for 14–21 days restored a) the competence to escape aversive stimuli; b) the motivation to operate in sucrose self-administration protocols; c) the dopaminergic response to sucrose consumption, evaluated measuring phosphorylation levels of cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS, by immunoblotting. ResultsLamotrigine administration restored the response to aversive stimuli and the motivation to operate for sucrose. Moreover, it reinstated NAcS DARPP-32 phosphorylation changes in response to sucrose consumption. LimitationsThe pro-motivational effects of lamotrigine that we report may not completely transpose to clinical use, since anhedonia is a multidimensional construct and the motivational aspects, although relevant, are not the only components. ConclusionsThis study shows antidepressant-like and pro-motivational effects of repeated lamotrigine administration in a rat model of depressive symptoms.

Efficacy of shared decision-making on treatment adherence of patients with bipolar disorder: a cluster randomized trial (ShareD-BD)

BackgroundShared decision-making (SDM) is a model of interaction between doctors and patients in which both actors contribute to the medical decision-making process. SDM has raised great interest in mental healthcare over the last decade, as it is considered a fundamental part of patient-centered care. However, there is no research evaluating the efficacy of SDM compared to usual care (CAU), as it relates to quality of care and more specifically treatment adherence, in bipolar disorder (BD).Methods/DesignThis is a 12-month multi-centre, cluster-randomized controlled trial comparing the efficacy of SDM to CAU. Adult BD patients (n = 300) will be eligible after stabilization for at least 4 weeks following an acute mood episode. The intervention will consist of applying the standardized SDM process as developed by the Ottawa Hospital Research Institute in order to choose the maintenance treatment of BD. A multidisciplinary team developed a decision aid “choose my long-term treatment with my doctor” for BD patients to clarify possible therapeutic options. Primary outcome will assess the patient’s level of adherence (based on hetero-evaluation) of ongoing treatment at 12 months. Secondary outcomes will assess the difference between the 2 groups of patients in terms of adherence to maintenance drug therapy based on other measures (self-assessment scale and plasma levels of mood stabilizers). Additionally, other dimensions will be assessed: decisional conflict, satisfaction with care and involvement in decision making, beliefs about treatment, therapeutic relationship, knowledge about information for medical decision and clinical outcomes (depression, mania, functioning and quality of life).The primary endpoint will be analysed without adjustment by comparison of adherence scores between the two groups using Student t-tests or Mann–Whitney tests according to the variable distribution. A set of secondary analyses will be adjusted for covariates of clinical interest using generalized linear mixed regression models.DiscussionThis will be the first study evaluating the effect of an SDM intervention on patient adherence in BD. This is also an innovative protocol because it proposes the development of an evidence-based tool that should help patients and clinicians to initiate discussions regarding the use of BD treatment.Trial registrationThe study has been registered with ClinicalTrials.gov as NCT03245593.

Real-world Effectiveness of Pharmacologic Treatments for the Prevention of Rehospitalization in a Finnish Nationwide Cohort of Patients With Bipolar Disorder

ImportanceMood stabilizers and antipsychotics are the main maintenance treatments for bipolar disorder. Lithium is considered to be the most effective mood stabilizer, but very little is known about overall health outcomes associated with specific treatments and the comparative long-term effectiveness of specific psychotropics or routes of administration in the prevention of rehospitalizations.ObjectiveTo study the comparative effectiveness of pharmacologic treatments in the prevention of rehospitalization in a nationwide cohort of patients with bipolar disorder.Design, Setting, and ParticipantsThis cohort study examined the risk of psychiatric, cardiovascular, and all-cause hospitalization from January 1, 1987, to December 31, 2012, among all patients in Finland who had been hospitalized for bipolar disorder (N = 18 018; mean follow-up time, 7.2 years) using prospectively gathered nationwide databases for hospitalization and dispensed medications. The primary analysis was within-individual analysis, in which each individual was used as his or her own control to eliminate selection bias. The study adjusted for the effect of concomitant psychotropic medications, duration of illness, and the temporal orders of exposure and nonexposure periods. Statistical analysis was conducted from January 1, 1996, to December 31, 2012.Main Outcomes and MeasuresAdjusted hazard ratios (HRs) for rehospitalization were calculated.ResultsAmong the cohort (9558 women and 8460 men; mean [SD] age, 46.6 [17.0] years), 9721 patients (54.0%) had at least 1 psychiatric rehospitalization. In comparison between use and no use among specific agents reaching nominal statistical significance, risperidone long-acting injection (HR, 0.58 [95% CI, 0.34-1.00]), gabapentin (HR, 0.58 [95% CI, 0.44-0.77]), perphenazine long-acting injection (HR, 0.60 [95% CI, 0.41-0.88]), and lithium carbonate (HR, 0.67 [95% CI, 0.60-0.73]) were associated with the lowest risk of psychiatric rehospitalization. Concerning all-cause hospitalization, lithium (HR, 0.71 [95% CI, 0.66-0.76]) was associated with the lowest risk. The most frequently used antipsychotic treatment, quetiapine fumarate, showed only modest effectiveness (risk of psychiatric rehospitalization: HR, 0.92 [95% CI, 0.85-0.98]; risk of all-cause hospitalization: HR, 0.93 [95% CI, 0.88-0.98]). Long-acting injections were associated with substantially better outcomes compared with identical oral antipsychotics (risk of psychiatric rehospitalization: HR, 0.70 [95% CI, 0.55-0.90]; risk of all-cause hospitalization: HR, 0.70 [95% CI, 0.57-0.86]). Results from sensitivity analyses showed consistent beneficial effects only for lithium and for long-acting injections compared with their oral counterparts.Conclusions and RelevanceLithium was the most effective mood stabilizer, and long-acting injections the most effective antipsychotics, in preventing hospitalization due to mental or physical illness.

Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates

Although antidepressants (ADs) are widely used in bipolar depression, there is weak evidence for their effectiveness and safety in this condition. Furthermore, there is a paucity of studies on the risk-benefit ratio of AD maintenance treatment in bipolar disorder (BD). We compared rehospitalization rates of patients with BD-I depressive episode who were discharged with mood stabilizers (MSs) and/or atypical antipsychotics (AAPs) with or without adjunctive AD. Ninety-eight patients with BD-I who were hospitalized with a depressive episode between 2005 and 2013 were retrospectively followed for 6-months and 1-year rehospitalization rates, as well as time to rehospitalization, according to treatment at discharge: MSs and/or AAPs with or without AD. Multivariable survival models adjusted for covariates known to influence rehospitalization were conducted. Six-months and 1-year rehospitalization rates were significantly lower in the adjunctive-AD treatment group compared to the no-AD group (9.2% vs. 36.4%, P = .001, power = 0.87 and 12.3% vs. 42.4%, P = .001, power = 0.89, respectively). Time to rehospitalization within 6-months and 1-year was significantly longer in the adjunctive-AD treatment group (169.9 vs 141 days, P = .001 and 335.6 vs 252.3 days, P = .001, respectively). Adjunctive-AD treatment at discharge reduced significantly the adjusted risk of rehospitalization within 6-months (HR = 0.081, 95% CI: 0.016–0.412, P = 0.002) and 1-year (HR = 0.149, 95% CI: 0.041–0.536, P = 0.004). Moreover, adjunctive-AD treatment did not increase rehospitalization rates of manic episode. In conclusion, adjunctive-AD therapy to MS/AAP at discharge from BD-I depressive episode hospitalization is associated with a lower rate of and a longer time to rehospitalization during a 1-year follow up period.

Second Generation Long-Acting Antipsychotics in the Treatment of Bipolar Disorder: A Clinical Viewpoint

Bipolar Disorder (BD) is a severe, chronic and disabling condition. The gold standard of treatment is lithium, but the introduction of Second Generation Long-Acting Antipsychotics (SGA-LAIs) has been addressed several problems in the administration of oral SGAs in BD such as the patient’s adherence to the treatment. The aim of this commentary was to provide an overview of the use of SGA-LAIs in the treatment of BD. All considered, the use of SGA-LAIs such as Risperidone Long-Acting and Aripiprazole Long-Acting may have an important impact on the maintenance treatment of BD both in monotherapy or in association with mood stabilizers. In our opinion, the treatment with a SGA-LAI should be initiated as early as possible in BD, especially when non-adherence is suspected. Moreover, as personality disorders (PD) and BD may often coexist, it is worthy to note that the PD-BD comorbidity may further decrease treatment adherence and, therefore, we believe that the early use of a SGA-LAI both in monotherapy or in association with mood stabilizers may dramatically improve the compliance and the overall outcomes in such cases. However, he safety profile should be always kept in mind when choosing an SGALAI in the treatment of BD.

Attitudes toward antipsychotic treatment among patients with bipolar disorders and their clinicians: a systematic review.

IntroductionAntipsychotics are recommended as first-line therapy for acute mania and maintenance treatment of bipolar disorder; however, published literature suggests their real-world use remains limited. Understanding attitudes toward these medications may help identify barriers and inform personalized therapy. This literature review evaluated patient and clinician attitudes toward the use of antipsychotics for treating bipolar disorder.Materials and methodsA systematic search of the Cochrane Library, Ovid MEDLINE, Embase, and BIOSIS Previews identified English language articles published between January 1, 2000, and June 15, 2016, that reported attitudinal data from patients, health care professionals, or caregivers; treatment decision-making; or patient characteristics that predicted antipsychotic use for bipolar disorder. Results were analyzed descriptively.ResultsOf the 209 references identified, 11 met the inclusion criteria and were evaluated. These articles provided attitudinal information from 1,418 patients with bipolar disorder and 1,282 treating clinicians. Patients’ attitudes toward antipsychotics were generally positive. Longer duration of clinical stability was associated with positive attitudes. Implementation of psychoeducational and adherence enhancement strategies could improve patient attitudes. Limited data suggest clinicians’ perceptions of antipsychotic efficacy and tolerability may have the greatest impact on their prescribing patterns. Because the current real-world evidence base is inadequate, clinician attitudes may reflect a relative lack of experience using antipsychotics in patients with bipolar disorder.ConclusionAlthough data are very limited, perceived tolerability and efficacy concerns shape both patient and clinician attitudes toward use of antipsychotic drugs in bipolar disorder. Additional studies are warranted.

Bupropion Maintenance Treatment in Refractory Bipolar Depression: A Case Report.

Background:The optimal duration of antidepressant treatment in bipolar depression appears to be controversial due to a lack of quality evidence, and guideline recommendations are either vague or contradictive. This is especially true for second line treatments such as bupropion that had not been subject to rigourous long term studies in Bipolar Disorder.Case presentation:We report the case of a 75 year old woman who presented with treatment refractory bipolar depression. Because of insufficient response to previous mood stabilizer treatment and refractory depressive symptoms, bupropion was added to venlafaxine and lamotrigine. From there onwards, the patient improved continuously without experiencing deterioration of depression or a switch into hypomania. Our patient being on antidepressants for allmost four years experienced an obvious benefit from longterm antidepressant administration.Conclusion:Noradrenergic/dopaminergic mechanisms of action may play a more prominent role in bipolar depression, and may still be underused as a therapeutic strategy in the acute phase as well as in long-term maintenance in at least a subgroup of bipolar patients. There is still a lack of evidence from RCTs, but this case report further supports antidepressant long-term continuation and the usefulness of a noradrenergic/dopaminergic antidepressant in the acute and maintenance treatment of bipolar disorder.

Clinical vignette – Aripiprazol long acting injection monotherapy as long-term treatment for bipolar disease

IntroductionOver the last decade a number of effective maintenance treatments for bipolar disorder (BPD) have been developed. Lithium remains the best-established option, but valproic acid, lamotrigine, olanzapine, and quetiapine are also effective maintenance drugs. However, oral administration contributes to lower adherence rates with these drugs. In the United States and Europe, aripiprazole is approved for the acute management of manic and mixed episodes and maintenance in BPD. It presents the advantage of a low risk of metabolic side effects, sexual dysfunction, and sedation, which can facilitate treatment adherence and help improve clinical outcomes.ObjectivesThe authors present an illustrative case on which aripiprazol long acting injection monotherapy was effective as maintenance treatment in a patient with long history of BPD with several hospital inpatient admissions and very poor therapeutic adherence.MethodsCase report based on the patient's file. Narrative review of articles available in PubMed about the use of aripiprazol in BPD.ResultsFor this patient, aripiprazol long acting injection has proved to be an excellent choice for long-term treatment of BPD. The once-a-month injection promotes therapeutic adherence, which in this case was combined with involuntary outpatient treatment, ensuring therapeutic compliance.ConclusionsAripiprazol has been shown to be safe and effective in the maintenance treatment in BPD. It shows similar efficacy and a superior tolerability profile when compared with other well-established treatments. Further studies are needed, warranted by its potential advantages, particularly on patients with poor insight and adherence.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines

BackgroundLithium is an effective mood stabilizer that is used principally for the management of bipolar disorder (BD). Its administration is complex and often requires sophisticated management and assiduous monitoring. When considering the use of lithium therapy for bipolar disorder, clinicians are advised to refer to recommendations outlined in clinical practice guidelines (CPGs); but because of varying emphases placed by different international CPGs, recommendations addressing the practical use of lithium lack consistency. MethodIn order to inform clinicians of optimal lithium therapy for bipolar disorder, we compared and synthesized recommendations for the treatment of bipolar disorder made by recognized CPGs internationally. We conducted a search of the literature and extracted guidance across multiple clinical issues, including clinical indications, disorder subtypes, additional uses, special populations, practical aspects, and side effects. ResultsCollectively, CPGs consider lithium most robustly as a first-line intervention for maintenance treatment of bipolar disorder and strongly for the treatment of mania, with relatively modest support for the management of acute bipolar depression. Additionally, there is consensus across the CPGs that lithium tangibly reduces the risk of suicide. Generally, CPGs provide guidance on the many facets of initiating and maintaining patients on lithium therapy, but individually the CPGs varied in terms of depth and practical guidance they provide across these areas. However, consensus was established across many key areas of practice such as the ideal lithium plasma concentration for maintenance and monitoring (0.6–0.8mmol/L), along with the need for regular monitoring of renal and endocrine function. However, with more complex aspects (e.g., atypical presentations) and in special populations (e.g., youth; pregnancy and post-partum; older adults), guidance varied considerably and clear consensus recommendations were more difficult to achieve. In younger adults desirable plasma lithium levels of 0.6–0.8mmol/L can perhaps be achieved with comparatively lower doses and in the very elderly it may be prudent to target lower plasma levels in the first instance. These are important practical points for consideration that, along with many others offered throughout the article, should assist clinicians in dissecting the more complex aspects of management with greater precision. LimitationsThis review was limited to CPGs written in English. CPGs are themselves limited by reliance on evidence that often has little resemblance to real-world presentations. An important area that is not sufficiently addressed in the CPGs is clear guidance on the cessation of lithium therapy. ConclusionsFurther research is needed on many aspects of lithium therapy and this alongside existing knowledge needs to be used more consistently to inform CPGs, which should also incorporate empirical evidence and clinical experience. The recommendations in this paper provide a useful synthesis of guidance available currently.

Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study

BackgroundThere is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine.Methods and FindingsWe conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64–3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45–0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45–0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47–0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40–0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29–0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09–0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13–0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10–0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14–0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07–0.73; p = 0.013) were also reduced relative to lithium. However, rates of greater than 15% weight gain on valproate, olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31–2.01; p < 0.001, olanzapine HR 1.84; 95% CI 1.47–2.30; p < 0.001, quetiapine HR 1.67; 95% CI 1.24–2.20; p < 0.001) than in individuals prescribed lithium, as were rates of hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06–1.87; p = 0.017). We found no significant difference in rates of chronic kidney disease stage 4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or hepatotoxicity. Despite estimates being robust following sensitivity analyses, limitations include the potential for residual confounding and ascertainment bias and an inability to examine dosage effects.ConclusionsLithium use is associated with more renal and endocrine adverse events but less weight gain than commonly used alternative mood stabilizers. Risks need to be offset with the effectiveness and anti-suicidal benefits of lithium and the potential metabolic side effects of alternative treatment options.

Depot aripiprazole as maintenance treatment in bipolar disorder: Report of a case

IntroductionRecently, depot aripiprazole was approved as a maintenance treatment for schizophrenia. However, long-acting antipsychotics has not been established efficacy in manic episode or maintenance treatment of bipolar disorder.AimsDescribe a clinical case of multiresistant bipolar disorder.MethodsThirty-nine years old male, diagnosed since 8 years ago with bipolar disorder, current episode manic with psychotic symptoms, admitted to Acute Psychiatrist Unit. It was his seventh internment. He was dysphoric, had insomnia, and showed many psychotic symptoms like grandiose delusions and delusions of reference. He thought he was a famous painter from nineteenth century.His disorder was refractory to mood stabilizers monotherapy and to many neuroleptic and, like olanzapine 30 mg/day, depot risperidone, zuclopenthixol, haloperidol, palmitate paliperidone, He was on treatment with lithium 1200 mg/day (lithemia 0.62 prior to admission) and oral aripiprazole 15 mg/day that he was not taking regularly. Poor compliance to oral treatment. No awareness of illness.Resultsduring the patient admission, we started long-acting aripiprazole 400 mg per 28–30 days. First 3 days he persisted dysphoric, hostile, and showing delusions of mind being read. From the fourth day, delusions disappeared and later he was calmer and more friendly, He was discharged 9 days later fully euthymic.For 6 months follow-up, the patient came once a month to community center for aripiprazole injection and he was taking lithium regularly. Last lithemia 0.65 mEQ/L.ConclusionLong-acting antipsychotics, like depot aripiprazole could be a useful alternative to oral medication, specially when there is no awareness of illness and there is low adherence to oral treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Use of antidepressants in maintenance phase of patients with bipolar disorder in an outpatient setting

IntroductionGuidelines for the maintenance treatment of bipolar disorder discourage the use of antidepressants chiefly on grounds of unproven efficacy and risk if mania for bipolar I. However, for patients stabilised on an antidepressant, naturalistic data support its continued use.AimThe aim is to describe use of antidepressants in patients with bipolar disorder in remission seen at an outpatient clinic in Singapore.MethodsThe case notes of patients with bipolar disorder in remission, seen by psychiatrist in an outpatient psychiatric clinic in a general hospital unit from December 2014 to March 2015 were studied. Data describing the age, sex, type of bipolar disorder and psychotropic medications prescribed, was obtained.ResultsForty-two patients were included, of which 13 (31%) were male and 29 (69%) were female. The age ranged from 23 to 82, with mean age of 47 years. Of these 17 (40%) had bipolar I and 25 (60%) had bipolar II. Antidepressant use for maintenance treatment was present in 19 out of 42 (45%) of these patients; of these 7 out of 17 (41%) were bipolar 1 and 12 out of 25 (48%) were bipolar II. Eighteen out of the 19 (95%) patients who were prescribed antidepressants were on combination treatment with mood stabilizers. Antidepressant type included SSRI (37%), NDRI (37%), SNRI (10.5%), TCA (10.5%), NASSA (5%).ConclusionAlmost half of patients with bipolar disorder managed in an individual practice were on antidepressants together with mood stabilisers. They remained in remission with combination treatment, which did not seem to jeopardise their condition.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Use of lithium in acute mania in adolescents

The aim of the present study was to investigate whether the use of lithium followed recommended practice in acutely manic adolescent inpatients. This study was a 12-month retrospective review of patients with manic episode admitted to Bakırköy Mazhar Osman Mental Health and Neurological Diseases Education and Research Hospital. Length of stay, medication data, serum levels and adverse effects were recorded for patients who started lithium treatment within average of 7 days of admission (n = 52). Average length of stay was 23.63 (SD = 17.6). The maximum dose prescribed within 24 h of starting treatment was 721.15 mg (SD = 239.5). The maximum daily dose was reached in an average of 7 days to 1136.5 mg (SD = 336.4). The average time after starting treatment until the first recorded serum level was 5 days. The average serum level reached was 0.5 mEq/L (SD = 0.22), which was raised to 0.6 mEq/L (SD = 0.3) at discharge with an average daily dose of 1038.46 mg (SD = 460). In 8 admissions (15.4%), one adverse effect was recorded that could have been related to lithium treatment but adverse events did not lead to discontinuation of drug. The literature supports that rapidly attained high serum levels are associated with positive outcomes. In this current study, clinicians used a relatively slow dose titration and lower serum levels were obtained suggesting that lithium was not considered as a primary agent for treating mania. Taking advantage of lithium especially for the maintenance treatment of bipolar disorder and tolerability may have driven these findings.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Clinical vignette – aripiprazol long acting injection monotherapy as long-term treatment for bipolar disease

Introduction Over the last decade a number of effective maintenance treatments for bipolar disorder (BPD) have been developed. Lithium remains the best-established option, but valproic acid, lamotrigine, olanzapine, and quetiapine are also effective maintenance drugs. However, oral administration contributes to lower adherence rates with these drugs. In the United States and Europe, aripiprazole is approved for the acute management of manic and mixed episodes and maintenance in BPD. It presents the advantage of a low risk of metabolic side effects, sexual dysfunction, and sedation, which can facilitate treatment adherence and help improve clinical outcomes. Objectives/aims The authors present an illustrative case on which aripiprazol long acting injection monotherapy was effective as maintenance treatment in a patient with long history of BPD with several hospital inpatient admissions and very poor therapeutic adherence. Methods Case report based on the patient's file. Narrative review of articles available in PubMed about the use of aripiprazol in BPD. Results For this patient, aripiprazol long acting injection has proved to be an excellent choice for long-term treatment of BPD. The once-a-month injection promotes therapeutic adherence, which in this case was combined with involuntary outpatient treatment, ensuring therapeutic compliance. Conclusions Aripiprazol has been shown to be safe and effective in the maintenance treatment in BPD. It shows similar efficacy and a superior tolerability profile when compared with other well-established treatments. Further studies are needed, warranted by its potential advantages, particularly on patients with poor insight and adherence.