Several augmentation strategies have been used to improve symptomatology in patients not adequately responding to clozapine. Several randomised controlled trials (RCTs) have evaluated the efficacy of different strategies to augment clozapine. This systematic review and meta-analysis reviewed the available RCTs that have evaluated the clinical efficacy of various pharmacological agents, non-pharmacological strategies (occupational therapy, cognitive behaviour therapy), and somatic treatment [electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, etc.)] as augmenting agents to clozapine.

Data were extracted using standard procedures, and risk of bias was evaluated. Effect sizes were computed for the individual studies.

Forty-five clinical trials were evaluated. The pooled effect size for various antipsychotic medications was 0.103 (95% CI: 0.288–0.493, p < 0.001); when the effect size was evaluated for specific antipsychotics for which more than one trial was available, the effect size for risperidone was −0.27 and that for aripiprazole was 0.57. The effect size for lamotrigine was 0.145, and that for topiramate was 0.392. The effect size for ECT was 0.743 (CI: 0.094–1.392). Risk of bias was low (mean Jadad score – 3.93). Largest effect sizes were seen for mirtazapine (effect size of 5.265). Most of the studies can be considered underpowered and limited by small sample sizes.

To conclude, based on the findings of the present systematic review and meta-analysis, it can be said that compared to other treatment strategies, clozapine non-responsive patients respond maximum to mirtazapine followed by ECT.

Obsessive–compulsive disorder (OCD) is a chronic psychiatric disorder that results in significant disability and substantial compromise in the quality of life. Until now, the role of repetitive transcranial magnetic stimulation (rTMS) has been primarily explored in individuals with treatment-resistant OCD. In this study, we investigated the safety and efficacy of rTMS as an early augmentation strategy in drug-free patients with OCD.

This is a randomized double-blind, placebo-controlled study that involved the administration of a total of 20 sessions of rTMS (active/sham) to drug-naïve OCD patients using a standard protocol (1-Hz; 20 trains [80 pulses/train]; 1600 pulses per session at 100% resting motor threshold) at supplementary motor area. All patients (active and sham) were started on escitalopram 10 mg/d, which was subsequently increased to 20 mg/d after 10 days.

Out of the 24 patients, 13 received active and 11 received sham rTMS. At the end of rTMS therapy, there was a substantial reduction (P = .001) in total Yale-Brown Obsessive–Compulsive Scale, obsessions (P = .030) and compulsions (P = .001) between the groups. Only few patients (N = 8) reported mild side effect with rTMS, local pain, and headache being the commonest. The study revealed large effect size (Cohen’s d = 1.6) of rTMS as an early augmentation strategy in drug-free patients of OCD.

rTMS is a safe and effective early augmentation strategy in the management of OCD. Larger randomized controlled trials are required to establish the therapeutic role of rTMS as early augmentation in OCD.

While the efficacy of repetitive transcranial magnetic stimulation (rTMS) in Major Depressive Disorder (MDD) is well established, the debate is still open in relation to bipolar depression and to a possible different effectiveness of high vs. low stimulation. The present study was aimed to assess and compare the efficacy and tolerability of different protocols of augmentative rTMS in a sample of patients with current Major Depressive Episode (MDE), poor drug response/treatment resistance and a diagnosis of MDD or bipolar disorder.

Thirty-three patients were recruited in a 4-week, blind-rater, rTMS trial and randomised to the following three groups of stimulation: (1) (n = 10) right dorsolateral prefrontal cortex (DLPFC) 1 HZ, 110% of the motor threshold (MT), 420 stimuli/day; (2) (n = 10) right DLPFC, 1 Hz, 110% MT, 900 stimuli/day; (3) (n = 13) left DLPFC, 10 Hz, 80% MT, 750 stimuli/day.

Twenty-nine patients completed the treatment, showing a significant reduction of primary outcome measures (HAM-D, MADRS and CGI-S total scores: t = 8.1, P < 0.001; t = 8.6, P < 0.001; t = 4.6, P < 0.001 respectively). No significant differences in terms of efficacy and tolerability were found between high vs. low frequency and between unipolar and bipolar patients. Side effects were reported by 21% of the sample. One of the 4 dropouts was caused by a hypomanic switch.

Augmentative rTMS appeared to be effective and well tolerated for the acute treatment of unipolar and bipolar depression with features of poor drug response/treatment resistance, showing a comparable effectiveness profile between protocols of high and low frequency stimulation.

Deep transcranial magnetic stimulation (dTMS) has been sanctioned by the United States Food and Drug Administration for treatment-resistant depression. In a retrospective cohort study, we evaluated response and effectiveness of dTMS in real-world practice, as an add-on treatment for resistant depression.

Forty adult outpatients suffering from depression, all taking psychiatric medications, underwent 20 dTMS treatments over a 4–6 week period. At baseline (T0), visit 10 (T1), and visit 20 (T2), the Clinical Global Impression-Severity (CGI-S) scale was administered, and the Clinical Global Impression Improvement (CGI-I) scale was completed at T1 and T2; the Hamilton Depression Rating Scale (HDRS-21) was administrated at T0 and T2 only. The patients also completed the Quick Inventory of Depressive Symptoms–Self-Report (QIDS-SR) at T0, T1, and T2.

Depressive symptoms (HDRS-21 total score) decreased significantly following treatment. The HDRS total score decreased from an average of 21.22 (± 6.09) at T0, to 13.95 (± 7.24) at T2. Correspondingly, at T2, 32.5% were responders to the treatment and 20% were in remission, based on the HDRS-21. Treatment was well tolerated, with a discontinuation rate of 7.5%. While depressive symptoms at baseline did not predict remission/response at T2, higher HDRS scores at T0 were associated with a larger decrease in depressive symptoms during the study.

Significant antidepressant effects were seen following 20 dTMS treatments, given as augmentation to ongoing medications in treatment-resistant depression. The findings suggest that among patients with TRD, the severity of the depressive episode (and not necessarily the number of failed antidepressant medication trials) is associated with a positive therapeutic effect of dTMS. Hence, the initial severity of the depressive episode may guide clinicians in referring patients for dTMS.

Outpatient interventions for adult anorexia nervosa typically have a modest impact on weight and eating disorder symptomatology. This study examined whether adding a brief online intervention focused on enhancing motivation to change and the development of a recovery identity (RecoveryMANTRA) would improve outcomes in adults with anorexia nervosa.

Participants with anorexia nervosa (n = 187) were recruited from 22 eating disorder outpatient services throughout the UK. They were randomised to receiving RecoveryMANTRA in addition to treatment as usual (TAU) (n = 99; experimental group) or TAU only (n = 88; control group). Outcomes were measured at end-of-intervention (6 weeks), 6 and 12 months.

Adherence rates to RecoveryMANTRA were 83% for the online guidance sessions and 77% for the use of self-help materials (workbook and/or short video clips). Group differences in body mass index at 6 weeks (primary outcome) were not significant. Group differences in eating disorder symptoms, psychological wellbeing and work and social adjustment (at 6 weeks and at follow-up) were not significant, except for a trend-level greater reduction in anxiety at 6 weeks in the RecoveryMANTRA group (p = 0.06). However, the RecoveryMANTRA group had significantly higher levels of confidence in own ability to change (p = 0.02) and alliance with the therapist at the outpatient service (p = 0.005) compared to the control group at 6 weeks.

Augmenting outpatient treatment for adult anorexia nervosa with a focus on recovery and motivation produced short-term reductions in anxiety and increased confidence to change and therapeutic alliance.

Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.

We conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.

Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions.

Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25–1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23–1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81–1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.08–1.30) and psychological (ES = 1.43, 95% CI 0.50–2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66–0.91) and psychological control (ES = 0.94, 95% CI 0.36–1.52).

Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.

In the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.