Mania associated with antidepressant treatment: comprehensive meta‐analytic review

Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta‐analytic review. Objective: To review available data pertaining to risk of mania–hypomania among bipolar (BPD) and major depressive disorder (MDD) patients with vs. without exposure to antidepressant drugs (ADs) and consider effects of mood stabilizers. Method: Computerized searching yielded 73 reports (109 trials, 114 521 adult patients); 35 were suitable for random effects meta‐analysis, and multivariate‐regression modeling included all available trials to test for effects of trial design, AD type, and mood‐stabilizer use. Results: The overall risk of mania with/without ADs averaged 12.5%/7.5%. The AD‐associated mania was more frequent in BPD than MDD patients, but increased more in MDD cases. Tricyclic antidepressants were riskier than serotonin‐reuptake inhibitors (SRIs); data for other types of ADs were inconclusive. Mood stabilizers had minor effects probably confounded by their preferential use in mania‐prone patients. Conclusion: Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased the risk of mania overall, with little protection by mood stabilizers.     

Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute,randomized, placebo‐controlled trials

Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo‐controlled trials.
Bipolar Disord 2010: 12: 116–141. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: To compare antipsychotic and mood stabilizer (MS) efficacy and tolerability in youth and adults with bipolar mania. Methods: Medline/PubMed search for studies including: (i) youth (< 18 years) or adults (≥ 18 years); (ii) bipolar I disorder; (iii) double‐blind, randomized, placebo‐controlled trial (DB‐RPCT); (iv) ≤ 12 weeks of treatment; and (v) calculable effect sizes (ES) and/or numbers needed to treat/harm (NNT/NNH) ± 95% confidence intervals (CI). Non‐overlapping 95% CIs determined significant group differences. Results: We identified nine DB‐RPCTs in youth (n = 1,609), 5 evaluating second‐generation antipsychotics (SGAs) (n = 1,140) and 4 evaluating MSs (n = 469). We also identified 23 DB‐RPCTs in adults (n = 6,501), 14 including SGAs (n = 3,297), 5 using haloperidol as an active comparator (n = 580), and 11 including MSs (n = 2,581). Young Mania Rating Scale scores improved significantly more with SGAs than MSs in youth (ES = 0.65, CI: 0.53–0.78 versus 0.24, CI: 0.06–0.41) and adults (ES = 0.48, CI: 0.41–0.55 versus 0.24, CI: 0.17–0.31). After excluding topiramate studies, SGAs had larger ES than MSs only in youth (ES = 0.65, CI: 0.53–0.78 versus 0.20, CI: 0.02–0.39), but not adults (ES = 0.48, CI: 0.41–0.55 versus 0.46, CI: 0.37–0.55). However, in adults SGAs had significantly larger ES regarding Clinical Global Impressions scores than MSs, even without topiramate (ES = 0.75, CI: 0.68–0.82 versus 0.24, CI: 0.07–0.41). Rates of response, remission, and discontinuation due to any reason compared to placebo were similar between medication and age groups, except for more favorable NNTs for remission with SGAs than MSs in adults after excluding topiramate. SGAs caused more weight gain than MSs in youth (ES = 0.53, CI: 0.41–0.66 versus 0.10, CI: ?0.12–0.33), but not in adults (ES = 0.13, CI: 0.05–0.22 versus 0.00, CI: ?0.08–0.08). However, results were heterogeneous and not significant in either age group after excluding topiramate. Nevertheless, SGA‐related weight gain was significantly greater in youth than adults. In youth, SGA‐related somnolence was greater than with MSs (NNH = 4.7, CI: 3.9–6.0 versus 9.5, CI: 6.3–23.5), and more likely than in adults (NNH = 7.1, CI: 6.1–8.8). Conversely, youth experienced less akathisia with SGAs than adults (NNH = 20.4, CI: 14.1–36.5 versus 10.2, CI: 8.1–13.7), likely due to lower doses/slower titration. Conclusions: In treating mania, potentially greater short‐term efficacy compared to placebo with SGAs versus MS needs to be balanced against increased adverse events, especially in youth.     

The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis

Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant‐induced mania: a systematic review and meta‐analysis.
Bipolar Disord 2010: 12: 702–706. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Antidepressant‐induced mania (AIM) has been associated with the serotonin‐transporter‐linked promoter region (5‐HTTLPR) polymorphism in some studies but not in others. We conducted a meta‐analysis of those studies and other studies of genetic predictors of AIM. Methods: MEDLINE‐based searches of genetic studies of AIM were conducted, and a meta‐analysis of six studies of 5‐HTTLPR was performed. Other polymorphisms were insufficiently studied to allow for meta‐analysis. Results: There was an association of the short (s) variant of 5‐HTTLPR and AIM [risk ratio (RR) = 1.35, 95% confidence interval (CI): 1.04–1.76, p = 0.02]. There was a higher frequency of s carriers (sl and ss genotypes) in those who developed AIM [RR = 1.38, 95% CI: 0.98–1.93), p = 0.06]. Conclusion: The 5‐HTTLPR polymorphism appears to have a moderate effect size association with AIM in patients with bipolar disorder.     

Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis

The new oral anticoagulants/non-vitamin K antagonists oral anticoagulants (NOACs) have recently reached the market and less is known about their safety in comparison to their efficacy. Therefore, we aimed to evaluate intracranial hemorrhage (ICH) risk with NOACs, the most feared adverse event of anticoagulation treatment. This is a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) comparing NOACs versus any control and reporting ICH events. Studies were searched through Medline and Cochrane Library (April 2014). Reviews and reference lists were also screened. Random effects’ meta-analysis was performed to derive pooled estimates expressed as relative risk (RR) and 95 % CI. Number needed to treat/harm (NNT/NNH) taking into account the baseline risk was also calculated. Heterogeneity was evaluated with I ² test. 18 RCTs evaluating 148,149 patients were included. NOAC significantly reduced ICH risk compared to vitamin K antagonists (VKA) (RR 0.44; 95 % CI 0.36–0.54; I ² = 37 %; NNT: 137 during 2 years) and to sequential treatment with low molecular weight heparin and VKA (RR 0.28; 95 % CI 0.12–0.65; I ² = 0 %; NNT: 463 patients during 7 months). Compared to placebo, NOACs were associated with an increased ICH risk (RR 3.31; 95 % CI 1.59–6.90; I ² = 0 %; NNH: 433 during 1 year). Results were similar for the different NOAC drugs and across the different clinical conditions. In patients requiring anticoagulation treatment, the risk of ICH is about half with the NOACs in comparison to standard antithrombotic treatment. This safer profile found in RCTs should be confirmed in real-world database studies.     

Analyses of mortality risk in patients with dementia treated with galantamine

Objective – To analyze mortality data from patients with Alzheimer’s disease (AD), Alzheimer’s plus cerebrovascular disease (AD + CVD) or vascular dementia (VaD). Methods – (1) Meta‐analysis of mortality data from double‐blind, placebo‐controlled, randomized trials; and (2) recontact study to collect additional longer term mortality data from previous galantamine trial participants. Results (meta‐analysis) – Across 12 trials (≤6 months duration), there was no increased risk of mortality associated with the use of galantamine (n = 4116) compared with that of placebo (n = 2386) (OR galantamine/placebo: 0.67, 95% CI 0.41–1.10). Results (recontact study) – Median survival was 79 months for patients with AD (n = 478) and 59 months for patients with AD + CVD (n = 180) or VaD (n = 145). Prolonged galantamine treatment (> vs ≤6 months) was not associated with decreased survival time (75 vs 61 months respectively; P = 0.02). Cox regression analyses were consistent with the Kaplan–Meier analyses. Conclusions – We found no short‐term or longer term evidence of increased risk of mortality associated with the use of galantamine in patients with AD, AD + CVD or VaD.     

Combination of Low‐Dose Bupivacaine and Opioids Provides Satisfactory Analgesia with Less Intraoperative Hypotension for Spinal Anesthesia in Cesarean Section

SUMMARY Aims: This meta‐analysis was undertaken to compare the three most common drug regimens of bupivacaine in spinal anesthesia for cesarean section: high‐dose bupivacaine (≥10 mg, HB), low‐dose bupivacaine (<10 mg, LB) and combination of low‐dose bupivacaine and opioids (LBO). Methods: Databases of MEDLINE, EMBASE, and Cochrane Library were searched (updated on October 30, 2011). Primary endpoints were the incidence of intraoperative hypotension and analgesia efficacy. Pooled risk ratio (RR) or standard mean difference and their 95% confidence intervals (95% CI) were calculated. A RR <1 indicates that LB or LBO regimen is associated with less intraoperative complications and better anesthesia or analgesia efficacy. Results: A total of 11 randomized controlled trials including 605 parturients were analyzed. Results of this meta‐analysis showed that compared with HB regimen, LB regimen decreased the incidence of intraoperative hypotension (RR = 0.64, 95% CI: 0.42–0.96) with less satisfactory analgesia (fixed model, RR = 1.50, 95% CI: 1.14–1.98). LBO regimen significantly reduced the incidence of intraoperative hypotension (RR = 0.52, 95% CI: 0.33–0.82) with reliable analgesia efficacy (RR = 2.56, 95% CI: 0.77–8.48). Conclusion: Compared with conventional HB regimen and LB regimen, LBO regimen not only reduced intraoperative hypotension but also provided reliable analgesia. Therefore, LBO regimen should be considered as the preferred drug combination for spinal anesthesia in cesarean section.     

Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis

Dierckx B, Heijnen WT, van den Broek WW, Birkenhäger TK. Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta‐analysis. Bipolar Disord 2012: 14: 146–150. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar major depression differs considerably from unipolar major depression with regard to the efficacy of treatment with antidepressants. In bipolar depression, response to treatment with antidepressants is disappointing. Whether response to electroconvulsive therapy (ECT) differs between bipolar and unipolar depression remains unclear. Therefore, this systematic review investigates the relative efficacy of ECT in both forms of depression. Methods: Relevant cohort studies were identified from a systematic search of the PubMed electronic database. Six studies were included in this meta‐analysis. Results: In this meta‐analysis, the overall remission rate was 50.9% (n = 402/790) for patients with unipolar depression and 53.2% (n = 168/316) for patients with bipolar major depression. A pooled odds ratio (OR) and confidence interval (CI) were calculated using random‐effects meta‐analysis with the Mantel–Haenzel method. This analysis shows similar efficacy of ECT in patients with unipolar and bipolar depression (OR = 1.08, 95% CI: 0.75–1.57). Conclusion: ECT appears to be equally effective for both bipolar and unipolar depression and the remission rates are encouraging, especially for bipolar depression.     

Meta-analysis of effectiveness and tolerability of treatment of mild to moderate depression with St. John's Wort

After anxiety, depression is one of the most common psychiatric diseases, showing a lifetime prevalence of 4.4 - 18 %. St. John's Wort is a herbal antidepressant combining a long tradition of use with well-proven medical research. We conducted a meta-analysis to review St. John's Wort's place in the treatment of depression. A comprehensive literature search was conducted for studies comparing effectiveness and tolerability of St. John's Wort with either placebo or synthetic antidepressant. Thirty studies met the inclusion as well as the quality criteria and were included in the meta-analysis. Four studies consisted of all three arms and were thus included in both analyses. Our results demonstrated a significant advantage for St. John's Wort compared to placebo (n = 2129, RR = 0.66, 95 % CI 0.57 - 0.78, p < 0.00001, NNT = 4.2 95 % CI 3.0 - 6.6, mean response: 53.3 vs. 32.7 %). Compared to synthetic antidepressants St. John's Wort demonstrated similar effectiveness (n = 2231, RR = 0.96, 95 % CI 0.85 - 1.08, p = 0.5, mean response: 53.2 % vs. 51.3 %). In the sub-group of mild to moderate depression, corresponding with the indication for St. John's Wort assigned by the German health authority, the herbal antidepressant showed better results against the synthetic antidepressants (n = 1166, RR = 0.85, 95 % CI 0.75 - 0.97, p = 0.01, NNT = 14.3, 95 % CI 8.3 - 100, mean response 59.5 vs. 52.9 %). This result viewed together with St. John's Wort's favourable side-effects profile, leading to a lower rate of drop-outs, suggests treatment with St. John's Wort should be attempted for milder forms of depression. Funnel plot analysis suggested publication bias could exist for the comparison with placebo. To put this in a perspective the fail-safe-N-test calculated that 423 studies with no effect would be needed to negate the presented result for placebo studies.     

Risk of incident depression in patients with Parkinson disease in the UK

Background: Non‐motor symptoms are not widely recognized in patients with Parkinson disease (PD). We sought to assess the incidence rate as well as the risk of depression in newly diagnosed patients with PD and to compare it to PD‐free controls. Methods: We conducted a population‐based follow‐up study with a nested case–control analysis based on data from the UK‐based General Practice Research Database (GPRD). We included PD patients ≥ aged 40 years with a first PD diagnosis between 1994 and 2005, and a matched comparison group free of PD. We assessed incidence rates (IRs) and relative risk estimates (odds ratios [ORs] with 95% confidence intervals [CI]). Results: The IR of depression in newly diagnosed PD in the UK community was 26.0 (95% CI 22.9–29.5) per 1000 person‐years. The risk of developing depression was increased almost twofold in patients with PD when compared to patients without PD (adj. OR 1.89; 95% CI 1.49–2.40). The increased relative risk was most pronounced in women and in individuals 40–69 years of age. Long‐term users of levodopa had an increased depression risk when compared to short‐term users. Conclusions: Patients with PD are at an approximately twofold increased risk of being diagnosed with depression compared to the PD‐free population.     

The heritability of bipolar affective disorder and the genetic relationship to unipolar depression

BACKGROUND: Twin studies of bipolar affective disorder (BPD) have either been small or have not used explicit diagnostic criteria. There has been little use of genetic model fitting and no analyses to explore the etiological overlap with unipolar depression (UPD). METHODS: Sixty-seven twin pairs, 30 monozygotic and 37 dizygotic, in which the proband had BPD were ascertained, and lifetime diagnoses were made using DSM-IV criteria. Univariate models were applied to estimate the contribution of additive genetic and environmental effects. Bipolar data were then combined with those from 68 monozygotic and 109 dizygotic pairs in which the proband had UPD. Two models were explored: a classic 2-threshold approach, in which BPD and UPD occupy the same continuum of liability but differ in severity, and a correlated liability model of mania and depression. RESULTS: Heritability of BPD was estimated at 85% (95% confidence interval [CI], 0.73-0.93) using narrow concordance and 89% (95% CI, 0.61-1.0) using broad concordance, with no shared environmental effects detected. A 2-threshold model was an unsatisfactory fit. Fitting a correlated liability model revealed a genetic correlation of 0.65 (95% CI, 0.58-0.75) between mania and depression and a correlation of 0.59 (95% CI, 0.15-0.84) for nonfamilial environment. Approximately 71% of the genetic variance for mania was not shared with depression. CONCLUSIONS: As defined by the DSM-IV, BPD is highly heritable. There are substantial genetic and nonshared environmental correlations between mania and depression, but most of the genetic variance in liability to mania is specific to the manic syndrome.     

Familial aggregation of Parkinson's disease in a multiethnic community‐based case‐control study

To assess the familial aggregation of Parkinson's disease (PD), we compared the cumulative incidence of PD among first‐degree relatives of PD cases and controls. We identified newly diagnosed patients with PD (n = 573) during 1994 to 1995 within Kaiser Permanente Medical Care Program of Northern California and recruited 496 cases (87%) for the case‐control study. Of 720 eligible controls matched by birth year and sex to cases, 541 (75%) agreed to participate. Information on family history of PD and other neurodegenerative diseases was obtained by in‐person structured interview. We used the reconstructed cohort approach that provides a better estimate of the risk. The cumulative incidence of PD was significantly higher among relatives of PD patients compared with relatives of controls (2.0 vs. 0.7%; relative risk (RR) = 3.4, 95% confidence interval (CI) 1.9–5.9; P = 0.0001). The degree of familial aggregation was higher among first‐degree relatives of Hispanic PD cases compared with Hispanic controls (3.7% vs. 0.4%; RR = 8.5, 95% CI 1.0–68.9) than it was among non‐Hispanic Caucasian cases and controls (2.0% vs. 0.8%; RR = 2.7, 95% CI 1.5–5.1; P = 0.02). The familial aggregation of PD was stronger among the siblings of PD cases (RR = 5.4, 95% CI 1.8–16.0) than among parents (RR = 2.7, 95% CI 1.3–5.2). The incidence and familial aggregation of PD is highest among Hispanics, warranting further studies of genetic and environmental risk factors in the Hispanic population. © 2010 Movement Disorder Society     

Augmentation of clozapine with a second antipsychotic - a meta-analysis

Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic – a meta‐analysis. Objective: To examine using meta‐analysis the effect of adding a second antipsychotic to established clozapine monotherapy. Method: A literature search was conducted in April 2011, and randomised placebo‐controlled double‐blind studies were identified. We performed a meta‐analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel‐plot analysis. Results: Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size ?0.239 (95% CI: ?0.452, ?0.026); P = 0.028). Meta‐regression of the effect of length of treatment on effect size showed no relationship (P = 0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR = 1.20, 95% CI 0.80–1.82). There was no evidence of publication bias. Conclusion: Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation.     

Meta‐analysis of early nonmotor features and risk factors for Parkinson disease

Objective:

To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population‐based screening.

Methods:

A systematic review and meta‐analysis of risk factors for PD.

Results:

The strongest associations with later diagnosis of PD were found for having a first‐degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65–3.93 and OR, 4.45; 95% CI, 3.39–5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10–3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55–3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39–0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta‐blockers, farming occupation, and well‐water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti‐inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results.

Interpretation:

The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them. ANN NEUROL 2012     

Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis

Purpose: Evaluate the clinical comparability of new antiepileptic drugs (AEDs) in partial refractory epilepsy. Methods: Systematic review of randomized trials (RCTs) comparing a new AED (add‐on treatment) with placebo or another AED. Primary outcomes: responder (≥50% seizure reduction) and withdrawal (tolerability) rates. Pooled estimates of odds ratios (ORs) and number needed treat/harm (NNT/NNH) taking into account baseline risk were derived by random‐effects meta‐analysis. Adjusted frequentist indirect comparisons between AEDs were estimated. Key Findings: Sixty‐two placebo‐controlled (12,902 patients) and eight head‐to‐head RCTs (1,370 patients) were included. Pooled ORs for responder and withdrawal rates (vs. placebo) were 3.00 [95% confidence interval (CI) 2.63–3.41] and 1.48 (1.30–1.68), respectively. Indirect comparisons of responder rate based on relative measurements of treatment effect (ORs) favored topiramate (1.52; 1.06–2.20) in comparison to all other AEDs, whereas gabapentin (0.67; 0.46–0.97) and lacosamide (0.66; 0.48–0.92) were less efficacious, without significant heterogeneity. When analyses were based on absolute estimates (NNTs), topiramate and levetiracetam were more efficacious, whereas gabapentin and tiagabine were less efficacious. Withdrawal rate was higher with oxcarbazepine (OR 1.60; 1.12–2.29) and topiramate (OR 1.68; 1.07–2.63), and lower with gabapentin (OR 0.65; 0.42–1.00) and levetiracetam (OR 0.62; 0.43–0.89). Significance: The differences found are of relatively small magnitude to allow a definitive conclusion about which new AED(s) has superior effectiveness. This uncertainty probably reflects the limitations of conclusions based on indirect evidence. The process of pharmacologic clinical decision making in partial refractory epilepsy probably depends more on other aspects, such as individual patient characteristics and pharmacoeconomics, than on available controlled randomized evidence.     

Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: A meta‐analysis

Introduction: High‐dose intravenous immunoglobulin (IVIg) is an evidence‐based treatment for multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). Recently, subcutaneous immunoglobulin (SC‐Ig) has received increasing attention. Methods: We performed a meta‐analysis of reports of efficacy and safety of SC‐Ig versus IVIg for inflammatory demyelinating polyneuropathies. Results: A total of 8 studies comprising 138 patients (50 with MMN and 88 with chronic CIDP) were included in the meta‐analysis. There were no significant differences in muscle strength outcomes in MMN and CIDP with Sc‐Ig (MMN: effect size [ES] = 0.65, 95% confidence interval [CI] = ‐0.31‐1.61; CIDP: ES = 0.84, 95% CI = ‐0.01‐1.69). Additionally SC‐Ig had a 28% reduction in relative risk (RR) of moderate and/or systemic adverse effects (95% CI = 0.11‐0.76). Conclusions: The efficacy of SC‐Ig is similar to IVIg for CIDP and MMN and has a significant safety profile. Muscle Nerve 55 : 802–809, 2017     

Placebo-corrected efficacy of modern nonenzyme-inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis

Purpose: Given serious concerns over the adverse effects of enzyme induction, modern nonenzyme‐inducing antiepileptic drugs (AEDs) may be preferable, provided they have similar efficacy as enzyme‐inducing AEDs. This is currently unclear. Methods: Therefore, we performed a meta‐analysis of the evidence to determine the placebo‐corrected efficacy of adjunctive treatment with modern nonenzyme‐inducing AEDs versus modern enzyme‐inducing AEDs that are on the market for refractory focal epilepsy. Key Findings: Of 322 potentially eligible articles reviewed in full text, 129 (40%) fulfilled eligibility criteria. After excluding 92 publications, 37 studies dealing with a total of 9,860 patients with refractory focal epilepsy form the basis for the evidence. The overall weighted pooled‐risk ratio (RR) in favor of enzyme‐inducing AEDs over placebo was 2.37 (95% confidence interval [CI] 1.77–3.18, p < 0.001) for at least 50% seizure reduction and 4.45 (2.26–8.76, p < 0.001) for seizure freedom. The corresponding weighted pooled RR in favor of nonenzyme‐inducing AEDs over placebo was 2.28 (95% CI 2.03–2.57, p < 0.001) for at least 50% seizure reduction and 3.23 (95% CI 2.23–4.67, p < 0.001) for seizure freedom. In a meta‐regression analysis in the same sample with at least 50% seizure reduction as outcome, the ratio of RRs for enzyme‐inducing AEDs (eight studies) versus nonenzyme‐inducing AEDs (29 studies) was 1.01 (95% CI 0.77–1.34, p = 0.92)). Similarly, the ratio of RRs for a seizure‐free outcome for enzyme‐inducing AEDs (six studies) versus nonenzyme‐inducing AEDs (19 studies) was 1.38 (95% CI 0.60–3.16, p = 0.43). Significance: Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the efficacy of adjunctive treatment with modern nonenzyme‐inducing AEDs is similar to that of enzyme‐inducing AEDs. Given the negative consequences of enzyme induction, our data suggest that nonenzyme‐inducing AEDs may be useful alternatives to enzyme‐inducing AEDs for treatment of refractory focal epilepsy.     

A systematic review of duloxetine and venlafaxine in major depression,including unpublished data

Schueler Y‐B, Koesters M, Wieseler B, Grouven U, Kromp M, Kerekes MF, Kreis J, Kaiser T, Becker T, Weinmann S. A systematic review of duloxetine and venlafaxine in major depression, including unpublished data. Objective: To determine the short‐term antidepressant efficacy and tolerability of duloxetine and venlafaxine vs. each other, placebo, selective serotonin reuptake inhibitors (SSRIs), and tri‐ and tetracyclic antidepressants (TCAs) in adults with major depression. Method: Meta‐analysis of randomised controlled trials identified through bibliographical databases and other sources, including unpublished manufacturer reports. Results: Fifty‐four studies including venlafaxine arms (n = 12 816), 14 including duloxetine arms (n = 4528), and two direct comparisons (n = 836) were analysed. Twenty‐three studies were previously unpublished. In the meta‐analysis, both duloxetine and venlafaxine showed superior efficacy (higher remission and response rates) and inferior tolerability (higher discontinuation rates due to adverse events) to placebo. Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs (OR = 1.20, 95% CI 1.07–1.35 and 1.38, 95% CI 1.15–1.66, respectively), and no differences in efficacy and tolerability to TCAs. Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine (OR = 1.53, 95% CI 1.10–2.13 and OR 1.79, 95% CI 1.16–2.78, respectively). Conclusion: Rather than being a first‐line option, venlafaxine appears to be a valid alternative in patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be indicated as a first‐line treatment.     

Predominant recurrence polarity among 928 adult international bipolar I disorder patients

Baldessarini RJ, Undurraga J, Vázquez GH, Tondo L, Salvatore P, Ha K, Khalsa H‐MK, Lepri B, Ha TH, Chang JS, Tohen M, Vieta E. Predominant recurrence polarity among 928 adult international bipolar I disorder patients. Objective: To test the hypothesis that patients with bipolar disorder (BPD) differ demographically and clinically within subgroups based on the predominant‐polarity of major recurrences. Method: We tested factors for association with predominantly (≥2 : 1) depressive vs. mania‐like episodes with 928 DSM‐IV type‐I BPD subjects from five international sites. Results: Factors preliminarily associated with predominant‐depression included: electroconvulsive treatment, longer latency‐to‐BPD diagnosis, first episode depressive or mixed, more suicide attempts, more Axis‐II comorbidity, ever having mixed‐states, ever married, and female sex. Predominant‐mania was associated with: initial manic or psychotic episodes, more drug abuse, more education, and more family psychiatric history. Of the 47.3% of subjects without polarity‐predominance, risks for all factors considered were intermediate. Expanding the definition of polarity‐predominance to ≥51% added little, but shifting mixed‐states to ‘predominant‐depression’ increased risk of suicidal acts from 2.4‐ to 4.5‐fold excess over predominant‐mania–hypomania, and suicidal risk was associated continuously with increasing proportions of depressive or mixed episodes. Conclusion: Subtyping by predominant‐polarity yielded predictive associations, including the polarity of first episodes and risk of suicide attempts. Such subtyping may contribute to improve planning of clinical care and to biological studies of BPD.     

Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials

BACKGROUND: Bipolar disorder (BD) is a leading cause of disability. Systematic reviews of randomized trials for the treatment of the maintenance phase of BD are lacking. OBJECTIVES: To determine the efficacy and tolerability of mood stabilizers and antipsychotics in the maintenance treatment of BD. METHODS: We systematically reviewed randomized controlled trials of licensed medications for the treatment of any phase of BD. We included randomized controlled trials comparing a medication to placebo or another medication. Comprehensive searches of electronic databases were conducted to March 2005. Outcomes investigated were relapse due to mania, depression or any mood episode, and withdrawal due to any reason or due to an adverse event. Data were combined through meta-analysis. RESULTS: Fourteen studies (n = 2,526) met the inclusion criteria. Lithium, lamotrigine, olanzapine and valproate semisodium each demonstrated evidence to support long-term use. Compared with placebo, all medications were more effective at preventing relapse because of any mood episode. Hazard ratios (HR) were 0.68 [95% confidence interval (CI) = 0.53-0.86] for lithium, 0.68 (95% CI = 0.55-0.85) for lamotrigine, and 0.82 (95% CI = 0.57-1.20) for valproate semisodium; for olanzapine, the risk ratio (RR) was 0.58 (95% CI = 0.49-0.69). Lithium and olanzapine significantly reduced manic relapses (HR = 0.53; 95% CI = 0.35-0.79 and RR = 0.37; 95% CI = 0.24-0.57, respectively). Lamotrigine and valproate semisodium significantly reduced depressive relapses (HR = 0.65; 95% CI = 0.46-0.91 and RR = 0.40; 95% CI = 0.20-0.82, respectively). Lithium significantly reduced manic relapses compared with lamotrigine (HR = 0.56; 95% CI = 0.34-0.92) and olanzapine significantly reduced manic relapses compared with lithium (RR = 1.69; 95% CI = 1.12-2.55). Withdrawal due to an adverse event was approximately twice as likely with lithium compared with valproate semisodium (RR = 1.81; 95% CI = 1.08-3.03) and lamotrigine (RR = 2.20; 95% CI = 1.31-3.70). There were few data for carbamazepine or medications given as adjunct therapy. CONCLUSIONS: Mood stabilizers have differing profiles of efficacy and tolerability, suggesting complementary roles in long-term maintenance treatment.     

Association of pharmacological treatments and real-world outcomes in borderline personality disorder

Objective

Most patients with borderline personality disorder (BPD) receive psychopharmacological treatment, but clinical guidelines on BPD lack consensus on the role of pharmacotherapy. We investigated the comparative effectiveness of pharmacological treatments for BPD.

Methods

We identified patients with BPD with treatment contact during 2006–2018 using Swedish nationwide register databases. By leveraging within-individual design, in which each individual was used as their own control to eliminate selection bias, we assessed the comparative effectiveness of pharmacotherapies. For each medication, we calculated the hazard ratios (HRs) for the following outcomes: (1) psychiatric hospitalization and (2) hospitalization owing to any cause or death.

Results

We identified 17,532 patients with BPD (2649 men; mean [SD] age = 29.8 [9.9]). Treatment with benzodiazepines (HR = 1.38, 95% CI = 1.32–1.43), antipsychotics (HR = 1.19, 95% CI = 1.14–124), and antidepressants (HR = 1.18, 95% CI = 1.13–1.23) associated with increased risk of psychiatric rehospitalization. Similarly, treatment with benzodiazepines (HR = 1.37, 95% CI = 1.33–1.42), antipsychotics (HR = 1.21, 95% CI = 1.17–1.26), and antidepressants (HR = 1.17, 95% CI = 1.14–1.21) was associated with a higher risk of all-cause hospitalization or death. Treatment with mood stabilizers did not have statistically significant associations with the outcomes. Treatment with ADHD medication was associated with decreased risk of psychiatric hospitalization (HR = 0.88, 95% CI = 0.83–0.94) and decreased risk of all-cause hospitalization or death (HR = 0.86, 95% CI = 0.82–0.91). Of the specific pharmacotherapies, clozapine (HR = 0.54, 95% CI = 0.32–0.91), lisdexamphetamine (HR = 0.79, 95% CI = 0.69–0.91), bupropion (HR = 0.84, 95% CI = 0.74–0.96), and methylphenidate (HR = 0.90, 95% CI = 0.84–0.96) associated with decreased risk of psychiatric rehospitalization.

Conclusions

ADHD medications were associated with a reduced risk of psychiatric rehospitalization or hospitalization owing to any cause or death among individuals with BPD. No such associations were found for benzodiazepines, antidepressants, antipsychotics, or mood stabilizers.