Clozapine [also via norclozapine] has a unique pharmacological profile (below) that is extensively detailed elsewhere.
ECT is an often effective adjunct in clozapine-resistant patients 
One RCT (n=18) indicated that the combination of clozapine with ECT was superior to monotherapy with either clozapine or ECT alone in patients with TRS. In a recent RCT, 10 of 20 patients (50%) responded to ECT along with clozapine when using a 40% reduction in symptoms criterion, although no responders were found in the clozapine monotherapy group (n=19). Nonresponders from the clozapine group subsequently received an 8-week open trial of ECT and 47% of patients responded. Although sample sizes in these trials were small, ECT may be a promising option for the short-term treatment of patients with clozapine resistant TRS. 
Addition of atypical antipsychotics to clozapine (CLZ):
“[the] data do not support the addition of an atypical antipsychotic with high-potency D2 [blockade] to CLZ, and this is confirmed by the observation that risperidone, the SGA with the strongest D2 blockade, demonstrated poor efficacy and high risk of side effects when added to CLZ. When drugs such as aripiprazole, a partial D2 agonist, and amisulpride, a D3/5-HT7 antagonist, have been added to CLZ, a certain degree of symptoms improvement was seen, thus it seems that increasing the D2 occupation might be ineffective or deleterious rather than beneficial”
Augmentation of CLZ with amisulpride in treatment-resistant schizophrenia has been evaluated in open-label trials that reported a significant reduction of primary and secondary outcome measures. A significant improvement of residual depressive symptoms, global functioning and quality of life, but not positive and negative symptoms, was shown in a randomized, double-blind, placebo-controlled trial on a small sample of partial responder schizophrenia patients treated with CLZ; however, high rates of adverse effects, such as increase in prolactin serum levels, tremor, akathisia and bradykinesia were documented
Aripiprazole add-on to CLZ did not offer statistically significant advantage over placebo treatment for total symptom severity, although it was superior to placebo in improving negative, positive symptoms and overall clinical state, whereas no significant effect on cognitive symptoms was observed. Concerning metabolic effects, the combination of aripiprazole plus CLZ resulted in significant reduction in body weight, body mass index, fasting cholesterol and triglycerides levels
There is only limited evidence for the combination of clozapine with a second antipsychotic and no combination strategy is superior to the other.
The antidepressant augmentation of CLZ remains unclear with inconsistencies reported:
– Antidepressants with predominant serotonergic effects, such as fluoxetine, have not shown beneficial effects, whereas mirtazapine and duloxetine add-on showed better results.
– Only one RCT showed that citalopram was effective on total symptoms severity.
– The positive effect reported with fluvoxamine add-on may be due to its activity towards sigma receptors or through the inhibition of CYP1A2 metabolism of CLZ, thus increasing CLZ and reducing norclozapine levels:
The increase of CLZ plasma levels might partially explain the positive effects reported with fluvoxamine augmentation; moreover, the risk of side effects also proportionally increases. Fluvoxamine added to CLZ has also been shown to decrease plasma levels of norclozapine, a toxic metabolite of CLZ, which is mainly associated with side effects, such as weight gain and metabolic syndrome in CLZ-treated patients
-Agomelatine augmentation was associated with improvement in clinical symptoms, overall psychopathological state and cognitive functioning; however, the small sample size, the lack of a control group, the open design and the non-blinded mode of rating do not allow for firm conclusions to be drawn.
In 2014, Bruno et al. conducted a 16-week, open-label, preliminary study, on 20 outpatients (9 men and 11 women) with a diagnosis of schizophrenia, who were stable on clozapine monotherapy at the highest tolerable dose (mean dose 430 mg/day) for at least one year. However, according to the Brief Psychiatric Rating Scale (BPRS) total scores >25, patients were considered partial responders to clozapine, due to the presence of residual symptoms. Concerning psychotic symptoms, at week 8, agomelatine augmentation of clozapine significantly improved Positive and Negative Syndrome Scale (PANSS) subscales “negative”, “general psychopathology”, as well as total score and overall clinical symptoms (measured by BPRS). At week 16, significant differences emerged in all PANSS domains, depressive symptoms (measured with the Calgary Depression Scale for Schizophrenia) and overall clinical symptoms. Regarding cognitive performances, at week 8, significant differences emerged only at Wisconsin Card Sorting Test (WCST) “perseverative errors”, whereas, at week 16, agomelatine treatment significantly improved performances on Stroop task and increased improvement on WCST “perseverative errors”. At endpoint, 9 subjects (64.3%) of the 14 completers responded to the coadministration of agomelatine (defined as a reduction in PANSS total score >25% between the baseline and follow-up ratings) and no patients worsened in clinical symptoms vs. baseline. The combination of agomelatine−clozapine was generally well tolerated and the most common adverse effects were gastrointestinal symptoms, headache and somnolence.
However, the small sample size, the lack of a control group, the open design, and the non-blinded mode of rating, the lack of clozapine therapeutic drug monitoring in addition to the need of longer-term, randomized, controlled studies do not allow for firm conclusions to be drawn. This may be a starting point for further research in this area as the improvement of cognitive performances in this trial was remarkable and warrants further investigations.
– See more here
– Lithium plus CLZ shows efficacy in schizoaffective disorder, it appears to be rather ineffective and potentially unsafe in schizophrenia
– Augmentation of valproate with CLZ has been evaluated in a single retrospective study; although it was reported as effective during the first month of treatment compared to CLZ monotherapy and CLZ associated with lithium on several symptom clusters (mood, anxiety and hostility), there is no sufficient evidence to advise the use of this augmentation strategy before further investigation in randomized clinical trials.
– Lamotrigine have shown more encouraging results, although evidence regarding its effective role in ameliorating symptoms in patients with inadequate response to CLZ is still a matter of debate.
A meta-analysis of five double-blind RCTs (total n=161), evaluating the effect of lamotrigine as an augmentor of clozapine, demonstrated that lamotrigine was superior to placebo in a total score for symptoms of psychosis (effect size=0.57,P<0.001), positive (effect size=0.34, P=0.04) and negative (effect size=0.43, P=0.008) symptoms of schizophrenia. However, two recent meta-analyses, in which an outlier study by Zoccali et al. with high effect size and small sample size was excluded, demonstrated that augmentation of clozapine with lamotrigine was not superior to placebo. Consistent with this result, Vayısog˘lu et al. found no beneficial effects of lamotrigine augmentation on psychopathology or cognitive functions in 34 patients with partial response to
Four double-blind RCTs have investigated topiramate as an adjunct to clozapine treatment, yielding discordant results. A meta-analysis of three of these trials found a trend towards a superior effect over placebo in reducing total symptom severity (n=89, effect size=0.75, P=0.07). However, the trend disappeared after exclusion of an outlier study by Afshar et al. with a relatively short follow-up period (8 weeks). Similar negative results of topiramate augmentation were obtained by Behdani et al. in a 17-week study in 80 patients. Topiramate augmentation of clozapine did not significantly decrease any of the three Positive and Negative Syndrome Scale (PANSS) subscales compared with placebo.
– Glutamatergic agents (glycine, D-serine, D-cycloserine etc) added to CLZ have not been effective or have worsened psychotic symptoms, suggesting that glycinergic drugs may interfere with the mechanism of action of CLZ.
NOTE: “Relative to effects in combination with typical or newer atypical antipsychotics, glycine site agonists have proved less effective when combined with clozapine. In double blind, placebo-controlled studies in which glycine (Evins et al., 2000) or D-serine (Tsai et al., 1999) has been added to clozapine, no significant beneficial response has been observed, while D-cycloserine is reported to lead to the worsening of symptoms when used in combination with clozapine (Goff et al., 1996).”
– The Ampakine CX516 showed improvement on negative symptoms and total symptom severity, although, as an experimental drug, it may not be suitable as augmentation strategy in clinical practice.
CX516, a positive modulator of the AMPA receptor, demonstrated superior efficacy for total symptom severity (effect size =1.35) and negative symptom severity (effect size =1.43) to placebo.However, the sample size of this study was very small (n=18) and the large improvement in negative symptoms with CX516 compared with placebo appears to reflect deterioration in the placebo group; thus, these findings should be interpreted with caution.
– In a double-blind, randomized, placebo-controlled trial, the NMDA antagonist memantine add-on to CLZ was associated with a significant improvement of both positive and negative symptoms; however, results need to be interpreted with caution due to the small sample size
In a double-blind RCT, memantine, a nonselective weak N-methyl-D-aspartate (NMDA) receptor antagonist, added to clozapine was associated with significant improvement of both positive and negative symptoms. Again, the sample size in this study was small (n=21), calling for a cautious interpretation.
– CLZ with ethyl eicosapentaenoic acid (E-EPA) has been encouraging (although controversial) thus further studies should clarify the real effectiveness and the best dose of E-EPA add-on.
EPA may be beneficial:
In one RCT, Eicosapentaenoic acid (EPA) showed better efficacy for total symptom severity than placebo in patients treated with clozapine
Estrogen may also be beneficial in women:
In a recent large-scale RCT in women with TRS (n=183), transdermal estradiol (200mcg), given as an adjunct to the ongoing antipsychotic therapy, showed superior efficacy for total symptom severity (effect size=0.31, P<0.01) and positive symptom severity (effect size=0.44, P<0.01) to placebo. Oestrogen may be a useful adjunctive treatment for women with TRS, but its therapeutic potential in men with schizophrenia remains unknown
– Minocycline add-on to CLZ has shown promise:
Minocycline, a second-generation tetracycline characterized by anti-inflammatory and neuroprotective properties, showed beneficial effects on negative symptoms, general outcome and executive functions in a longitudinal RCT on a sample of early phase schizophrenia patients treated with SGAs, including CLZ. Recently, minocycline add-on to CLZ in two treatment-resistant schizophrenia patients was effective in reducing residual positive and negative symptoms. In both studies, minocycline was well tolerated and safe, and these results warrant further investigation of add-on treatment for patients with schizophrenia.
- Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia.
Early studies with rTMS and tDCS demonstrated short-term improvements in verbal auditory hallucinations and/or negative symptoms of schizophrenia.
Barretto et al. conducted a controlled trial of CBT (n=21) in patients with clozapine-resistant TRS and found that CBT significantly improved general psychopathology compared with nonspecific psychosocial support (befriending) and that this effect persisted for 6 months. However, the sample size of this trial was small and it was not randomized. A recent meta-analysis of 12 RCTs (n=639) examining the effectiveness of CBT among outpatients with medication-resistant psychosis demonstrated beneficial effects of CBT on positive symptoms (effect size=0.47) and general symptoms (effect size=0.52)
A recent review found:
“…the most effective drug combinations were clozapine augmentation with 1) sodium valproate, 2) lithium, 3) amisulpride, and 4) quetiapine.”
- See also: Augmentation strategies in patients with schizophrenia who show partial response to clozapine treatment
See the next post for NMDA/glycinergic/AMPA augmentation.