Journal of Mental Health and Human Behaviour

: 2016  |  Volume : 21  |  Issue : 1  |  Page : 6--15

Strategies in clozapine-resistant schizophrenia: A literature review

Ganesh Kundadak Kudva, Dhanesh Kumar Gupta 
 Department of General Psychiatry, Institute of Mental Health, Hougang, Singapore

Correspondence Address:
Ganesh Kundadak Kudva
Block 103, Bishan Street 12, #02-274, Bishan


Treatment resistance to what is often deemed the last line of schizophrenia treatment, clozapine, is a burgeoning problem in psychiatric practice, with estimates of clozapine resistance standing at 40–70% of the treated population. This paper, a comprehensive review of available literature, looks at augmentation strategies to clozapine for such patients, with pharmacological and nonpharmacological modalities considered and reviewed. With a preponderance of open-label trials and case reports, our conclusion is that more research in this field via randomized clinical trials is crucial. Every case of clozapine resistance should be managed in an evidence-based and multidisciplinary manner, with augmentation only used once optimal dosage and duration of clozapine monotherapy is reached, and the psychosocial environment is optimized.

How to cite this article:
Kudva GK, Gupta DK. Strategies in clozapine-resistant schizophrenia: A literature review.J Mental Health Hum Behav 2016;21:6-15

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Kudva GK, Gupta DK. Strategies in clozapine-resistant schizophrenia: A literature review. J Mental Health Hum Behav [serial online] 2016 [cited 2021 May 13 ];21:6-15
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Full Text


The development of typical antipsychotics provided a crucial breakthrough in the treatment of schizophrenia, although their pronounced side effects, predominantly extrapyramidal, led to the subsequent discovery of the atypical antipsychotics, the first of which was clozapine.

Estimates vary for the proportion of nonresponders to antipsychotics, with estimates of 5–25% to 30–50%.[1],[2] Nonresponse was defined by Kane et al. (1996)[3] in his seminal paper on the subject using the following criteria [Table 1].{Table 1}

In this group of patients, clozapine has been shown, via multiple clinical trials, meta-analyses, and systematic reviews, to be the most effective treatment,[4],[5],[6],[7],[8] with significant reductions in relapse rates, better side effect profile, better compliance rates, and improvement on positive symptom scores on Positive and Negative Syndrome Scale (PANSS), albeit with little effect on negative symptom scores. Data from the 1997 American Psychiatric Association Practice Research Network showed that 7% of patients with a psychotic illness were on clozapine, with the main determinant for its use being treatment resistance.[9] Another study that looked at elderly East Asian patients found a clozapine prescription rate as high as 20.6%.[10]

However within this treatment-resistant group, an estimated 40–70% of subjects have limited response to clozapine, with limited response often defined as a <20–30% reduction in baseline Brief Psychiatric Rating Scale (BPRS) or PANSS score.[1] The term clozapine-resistant schizophrenia has been used to describe this condition, with Mouaffak et al.(2006)[11] suggesting the following criteria [Table 2].{Table 2}

It has been suggested, given the relatively high incidence of nonresponse, that clozapine should be viewed as a “stepping stone”[12] in the treatment process, with augmentation techniques being used once the therapeutic response is not forthcoming. Most studies set this duration as 3–6 months.

In this paper, we will review the existing literature to appraise strategies for those with limited response to clozapine. This literature review encompasses randomized controlled trials (RCTs), open-label trials, systematic reviews, and meta-analyses from 1990 to 2012 sourced from the PubMed, PsycInfo, and Google Scholar databases. Only articles that were either primarily in, or translated to English on these databases were utilized.

 Clozapine Augmentation Strategies

Rates of co-prescription of clozapine and a second agent vary by region, from a 35% co-prescription rate in Denmark [13] to an 85% co-prescription rate in Australia.[14] These fairly high rates represent the tendency of clinicians to aggressively augment clozapine in cases of resistance. Antipsychotics dominate the augmenting agents prescribed, with antidepressants the second most widely co-prescribed.


With a preponderance of open-label trials over randomized double-blind studies, the evidence base for augmentation with a second antipsychotic is weak,[15] with the open-label trials often showing benefit with augmentation, whereas the double-blind studies show no clear benefit.

Of the antipsychotics, amisulpride has the greatest benefit in the domains of positive and negative symptoms and improves the side effect profile of clozapine. Risperidone has shown some efficacy in ameliorating positive symptoms, and aripiprazole has benefit in the negative symptom domain. Aripiprazole offsets some of the metabolic side effects of clozapine.


The co-prescription of clozapine and risperidone has received greater academic focus than most of the other atypical antipsychotics, in part due to risperidone's potent D2 blockade, a receptor for which clozapine has low affinity. The use of risperidone as an augmentation agent has been strongly supported by an RCT that showed significant reduction in overall and positive symptom BPRS scores and a similar reduction in negative symptom scores that was sustained throughout the 12 weeks treatment duration, at a mean dose of 4.1 mg/day of risperidone,[16] a finding corroborated by another RCT conducted over 16 weeks,[17] Another study with a small sample size of 3 patients, illustrated the improvement in all domains of PANSS with little additional adverse effects.[18] However 2 large RCTs, which used between 3 and 4 mg/day of risperidone for shorter durations (<8 weeks), showed no significant improvement in overall symptoms with risperidone augmentation compared to placebo.[19],[20] A rise in fasting blood glucose levels [19] and prolactin levels [21] have been reported. Risperidone was also shown to reduce some of the cognitive improvements seen in clozapine monotherapy, especially in verbal learning and memory,[19] verbal fluency, attention, executive function, memory, and motor function.[21]


With its D2/D3 blocking properties, amisulpride has a complementary receptor profile to clozapine.[22] An open retrospective study [23] showed that amisulpride could have beneficial effects in ameliorating positive and negative symptoms in those with clozapine resistance. Within this study, a patient, having been treated with low doses of both clozapine and amisulpride, demonstrated improved mood and drive, and a reduction in psychotic symptoms. The combination of the two drugs also allowed for a 24% reduction in clozapine dose, and thus better side effect profile. A comparison trial of augmentation regimens showed the clozapine-amisulpride combination, at mean amisulpride doses of 440 mg/day, to be superior to that of clozapine-quetiapine, with mean quetiapine doses of 600 mg/day. There was an appreciable difference on BPRS seen as early as week 3 of trial,[22] with significant improvement in BPRS and clinical global impression (CGI) by week 8. A similar side effect profile was noted between the two strategies. Another study showed improvement in global psychopathology in amisulpride augmentation, with better results obtained at higher doses (600 mg/day).[24] One case report noted a significant reduction in both positive and negative symptoms and improvement in social function after 2 months of 1000 mg/day of amisulpiride.[25] In addition, amisulpride has been shown to reduce clozapine-induced hypersalivation.[26]


As a partial 5HT2 and D2 agonist, the use of aripiprazole in conjunction with clozapine has often been in the context of reducing the metabolic side effects of the latter. Augmentation with aripiprazole resulted in improvements in waist circumference,[27] body mass index (BMI), serum lipid (total and low-density lipoprotein [LDL]), and triglyceride levels in individuals on clozapine monotherapy.[28] Another study studying aripiprazole augmentation found that while fasting plasma glucose, high-density lipoprotein and triglyceride levels were not corrected by augmentation, there was a positive effect on body weight and LDL levels.[29] Another study also showed lowered serum prolactin levels with aripiprazole augmentation.[30]

While there may be improved metabolic parameters with aripiprazole augmentation, the overall effect on psychotic symptoms appears mixed, with minimal improvement in total and positive symptom domains on BPRS and PANSS,[27],[28],[29],[30] albeit with some alleviation of negative symptoms [30] for augmentation durations of 8, 16, and 6 weeks, respectively. However another study which augmented clozapine with aripiprazole for a longer duration (24 weeks) showed significant improvement in positive symptoms.[31] A significant worsening of anxiety and akathisia has been reported in some patients on aripiprazole augmentation regimen.[29] As an augmenting agent to clozapine, aripiprazole has not been shown to be superior to haloperidol regarding reducing overall symptoms of schizophrenia, but does lead to markedly less neuroleptic side effects.[32]


Ziprasidone monotherapy has comparable efficacy to clozapine in reducing PANSS scores, with a better metabolic and extrapyramidal side effect profile.[33] As an augmenting agent to clozapine, ziprasidone has been shown to at least be as effective as risperidone as an augmenting agent, with a less extrapyramidal side effects but a slight prolongation in QT-interval.[34]

 Other Antipsychotics

The evidence base for most other antipsychotics is weak. Olanzapine,[35] sulpiride,[36] and haloperidol [32],[37] have been found to be helpful in augmentation though much further research is needed.

The theoretical basis for augmentation with typical antipsychotics, especially high potency ones like Haloperidol is promising; by enhancing D2 receptor blockade, the augmenting agent can address the one “weakness” of clozapine, its low affinity for D2 receptors. An increase in D2 receptor occupancy from 55% to 79% on addition of haloperidol to clozapine has been demonstrated.[38] However conflicting evidence also seems to suggest that the relative inhibition of D4 receptors relative to D2 may have anti-aggression effects (such as seen with clozapine and asenapine),[39] a factor which is lost in Haloperidol augmentation. There is also a case report of worsened treatment tolerability and development of extrapyramidal side effects when 6 mg/day haloperidol was added on to 450 mg/day of clozapine.[25] The contradictory theoretical evidence and lack of sufficient clinical data goes against augmentation with haloperidol.

Pimozide has been shown not to improve BPRS, PANSS, or neurocognitive measures, and carries a significant risk of QTc prolongation and arrhythmia.[40]

Augmentation with the atypical antipsychotic sertindole was not superior to placebo and caused a significant worsening of psychosis in some subjects, and a slight QTc interval prolongation.[41]


The selective serotonin reuptake inhibitors

There are three potential benefits for the usage of selective serotonin reuptake inhibitors (SSRIs) in tandem with clozapine. These are:

All the SSRIs are, to varying degrees, inhibitors of the hepatic cytochrome (CYP) system. Clozapine, predominantly metabolized by CYP1A2, could thus have its serum levels increased by co-administration of SSRIs. About 70% of the variance in clozapine clearance seen in patients has been attributed to differential CYP1A2 activity [42]Clozapine, via its anti-serotoninergic effects, has been reported to worsen the Obsessive compulsive symptoms of some patients. The serotonergic agonism of SSRIs could alleviate this to some extent [43]The inherent antidepressant effects of SSRIs which could promote rehabilitation and social integration for individuals with chronic schizophrenia.


Fluvoxamine alters the pharmacokinetics of clozapine via CYP1A2 antagonism, thus increasing serum levels of clozapine at the expense of its metabolite, nor-clozapine. The clozapine level rise is proportional to the administered dose of fluvoxamine, with an estimated rise of 2–3 times with the addition of 25–50 mg of fluvoxamine.[44] However, there is great variation in the possible serum level rise,[45] and close monitoring is crucial.

A reduction of nor-clozapine levels results in an improved metabolic profile. A study of clozapine monotherapy patients versus those on fluvoxamine augmentation showed the latter group to have better triglyceride and serum glucose levels, with a lower BMI and nor-clozapine level at the end of the 12 weeks trial.[46] The rise of clozapine levels may increase the risk of seizures;[47] although thus far there are conflicting data that there is no increase in clinically evident seizures.[48]


Fluoxetine has relatively less effect on the pharmacokinetics of clozapine when compared to fluvoxamine, with available data showing either no effect,[49] or a slight rise, in clozapine levels.

A double-blind trial showed that fluoxetine is of no benefit, with no effect on positive, negative or obsessive-compulsive symptomatology, as an augmenting agent to clozapine.[50]


The use of sertraline with clozapine has been rarely evaluated, but the limited data suggests limited usage with potentially fatal side effects. One case study showed a paradoxical worsening of obsessive compulsive and psychotic symptoms, which were attributed to elevation of clozapine levels to supra-therapeutic levels (>700 ng/ml) and excessive anti-muscarinic effects.[51] However another paper has suggested that sertraline, at typical therapeutic doses, does not increase clozapine levels significantly and thus can be added safely to clozapine.[52]

A combination of clozapine and sertraline was suggested to be the cause of cardiac arrhythmia and sudden death in a young Caucasian man in one case report,[53] with sertraline's QT prolongation effect postulated to be the trigger for the fatal arrhythmia.

 Other Selective Serotonin Reuptake Inhibitors

Citalopram has been suggested as the antidepressant of choice for alleviation of depressive symptoms in clozapine-treated patients given its limited effect on serum clozapine levels.[54] Paroxetine, which is a CYP2D6 inhibitor, raises clozapine levels by 31%[52] and in co-administration would close monitoring. There is also a possibility of the development of anticholinergic syndrome,[55] with paradoxical worsening of psychosis.

 Non-Selective Serotonin Reuptake Inhibitor Antidepressants

The literature is fairly limited on non-SSRI antidepressants, with most studies focused on the amelioration of clozapine-related side effects rather than enhancement of clozapine's therapeutic effects. Amitriptyline has been reported to improve clozapine-induced sialorrhea, possibly by antagonism at the M4 muscarinic receptor; as well as nocturnal enuresis.[56]

The addition of 30 mg a day of mirtazapine for 8 weeks was shown to improve avolition and anhedonia.[57] Mirtazapine has also been shown to have a direct effect on cognition, with improved immediate and delayed recall in patients on combination therapy noted independently of any improvement in psychosis.[58] The co-administration of mirtazapine with clozapine results in statistically insignificant changes in clozapine levels [59] and is generally well-tolerated.

 Mood Stabilizers

The augmentation of clozapine with divalproex or lithium has been shown to result in early gains in the treatment of schizophrenia, with greater improvements in BPRS scores at the end of the 1st month of therapy compared to monotherapy.[60] There is also evidence to support augmentation with lamotrigine or topiramate. However unlike the treatment of bipolar mania, for which the addition of mood stabilizers to antipsychotics is well-established in clinical practice, there is no such compelling evidence that such a strategy would be effective in the management of treatment-resistant schizophrenia.[61]


The addition of carbamazepine to nonclozapine neuroleptics has been shown to alleviate suspiciousness, uncooperativeness, and excitement, albeit with no significant improvement in BPRS scores.[62] Clinical use with clozapine is not recommended, given the risk of agranulocytosis, due to a synergistic pharmacodynamic effect in causing bone marrow suppression.[63]


Lamotrigine aids the glutamate antagonism demonstrated by clozapine at the N-methyl-D-aspartate (NMDA) receptor. This effect has been demonstrated in animal models, where Phencyclidine-induced stereotypical behaviors and hyper-locomotion (an animal model for psychosis) were significantly reduced in the lamotrigine-clozapine group, compared to those treated with either drug alone.[64] This combination has been shown to result in significant improvement in global symptomatology scores [65],[66],[67] both early and late in therapy, with an effect that is rapidly attained and sustained for long periods.[68] Of note is that this augmentatory effect was not seen when lamotrigine was added to typical antipsychotics and to risperidone,[69] suggesting that the effect is independent of the neural dopamine pathways. Lamotrigine also augments the anti-aggression effects of clozapine, particularly verbal aggression.[70]

There is a small but important risk of Stevens-Johnson Syndrome, for which lamotrigine in augmentation needs to be started at a low dose and increased slowly with monitoring for skin manifestations,[71] with titration to clinical response. There is also a single case report of a tripling of clozapine levels in a patient on lamotrigine augmentation.[72]


Two placebo controlled, randomized trials showed topiramate to be an effective augmenting agent,[73],[74] and two others illustrated no benefit.[75],[76] In one of the trials that showed benefit, the effect of augmentation resulted only in improvements in the General Psychopathologic Symptom category on the PANSS subscale, with no effect on positive or negative symptoms.[73] Test subjects also reported memory impairment and demonstrated deficits in cognitive processing.

Perhaps the greatest potential for topiramate lies in its ability to induce weight loss, and thus offset some of the weight gains induced by clozapine therapy.[73]


The predominant indication in current practice for lithium augmentation of clozapine is for mood stabilizing effects. There is increasing evidence for use on clozapine re-challenge in patients with previous clozapine-induced neutropenia. In one study, the incidence of neutropenia on re-challenge was only 4% for lithium co-administered patients, compared to the 21% for monotherapy,[77] and lithium is estimated to result in a rise of white blood cell count by 2.0 × 109/L.[78] However, this latter use remains controversial, with conflicting reports that lithium addition has itself been reported to possibly increase the risk of agranulocytosis.[79]

Lithium appears to be of benefit as an augmenting agent in schizoaffective patients, with improvements even in negative symptom and cognitive domains, but not in those with schizophrenia, in whom negative symptoms paradoxically worsened and cognition declined mildly.[78] However, another study reported that 84% of clozapine-resistant schizophrenic patients demonstrated improvements with lithium augmentation.[80]

Neurologic sequelae such as tremors, involuntary movements, and seizures,[78],[80] reversible leukocytosis [81] and rhabdomyolysis [82] have been reported to occur in clozapine-lithium combination therapy.

 Valproic Acid and Divalproex

Valproic acid is indicated for use in prophylaxis against seizures in individuals on high doses, or with high blood levels of, clozapine.[83] However as an augmenting agent to clozapine for therapeutic effect, little research has been done thus far.

Divalproex (valproate semi-sodium) has shown promising effects in combination with clozapine (when compared to clozapine monotherapy), resulting in less weight gain, greater improvement in BPRS scores after 6 months of therapy, and reducing hostility and anxiety.[60] Molecular theories have posited that valproate augments clozapine by epigenetic modifications that modulate 5HT2A receptor activity.[84]

The combination of valproate and clozapine is safe and well-tolerated.[85]

 Other Modalities

Pharmacological modalities


The selective estrogen receptor modulator, raloxifene, was shown to be beneficial in a single case report, with a reduction in hallucinatory behavior and delusions after a 2 weeks trial of 60 mg/day of raloxifene.[86] These findings were linked to the observation that early menarche (and thus higher estrogen levels) is associated with a later onset of schizophrenia and better clinical outcome in affected women.[87]

Glycine, D-cycloserine, and CX516

The hypo-glutamatergic hypothesis postulates that inactivity at the glycine site of the NMDA receptor is responsible for the negative symptoms of schizophrenia. Hence, compounds that mimic the activity of NMDA at this site could be of benefit. One open trial, which augmented typical neuroleptics with glycine, showed benefit in 2 of 6 chronic schizophrenic patients, with minimal gastrointestinal side effects.[88] However, rather surprisingly, glycine has been shown to interfere with the action of clozapine when used as an augmenting agent,[89],[90] even going as far as to negate the therapeutic effects of clozapine. However, this negation of effect does not extend to typical neuroleptics when augmented with glycine.[89] Similar findings have been observed with D-cycloserine, which shares a similar mode of action to glycine.[91] However the ampakine CX516, which positively modulates the glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor complex, has been shown to improve attention and memory in 4 weeks trial with clozapine.[92]

Donepezil and memantine

Donepezil, which reduces psychotic symptomatology in patients with dementia, has been used to augment clozapine in nondemented chronic schizophrenic patients with modest results. A small 18 weeks trial showed a slight improvement in the general symptomatology component of the PANSS scale, with no improvement in positive or negative symptom domains.[93] Memantine, a weak NMDA antagonist, partially ameliorates positive and negative symptoms when used with clozapine.[94]


Gingko augmentation has generally been viewed with much promise given its well-known cognitive-enhancing effects. Its mode of action has been postulated to involve free-radical scavenging and it has been shown to augment the effects, especially against positive symptoms, of typical neuroleptics like haloperidol.[95] However interestingly, the addition of 120 mg/day of gingko extract for 12 weeks was shown to improve negative symptoms in clozapine resistant schizophrenics, with little effect on positive symptoms.[96]


The phospholipid hypothesis, which postulates that a genetically determined abnormality of phospholipid metabolism in the central nervous system leads to schizophrenia, has lent credence to the notion of omega-3-fatty acid augmentation. A study by Peet et al. showed strong improvement clinically at 12 weeks with augmentation with 2 g/day of ethyl-eicosapentenoic acid when compared to placebo.[97] However, this effect appeared to be partially lost once the dose was increased to 4 g/day.

In addition, omega-3-triglycerides, at doses at or above 2 g/day, have also been shown to reduce the mean serum triglyceride levels,[97] by up to 22% in one study,[98] albeit with no obvious effect on total cholesterol and LDL levels.


Repetitive transcranial magnetic stimulation

Low frequency 1 Hz repetitive transcranial magnetic stimulation (rTMS) to the left temporoparietal region, a region whose hyperactivity has been shown to result in auditory hallucinations, has been postulated to reduce the severity of such experiences.[99] In a placebo-controlled trial studying the effect of rTMS on positive symptoms in clozapine-resistant patients, significant improvements were seen in both the rTMS and sham stimulation group at the end of therapy, albeit with greater long-term benefit in the rTMS group.[99] Another study showed benefit only in general psychopathology but not on refractory hallucinations.[100]

Electroconvulsive therapy

A combination of electroconvulsive therapy (ECT) and an antipsychotic has been shown have a rapid onset of action and to be more effective than either agent alone, in the management of treatment-resistant schizophrenia.[101],[102] The exact mode of action by which this occurs is not known but is postulated to be via increased blood-brain barrier permeability. ECT augmentation of clozapine has been shown to be more effective in schizoaffective disorder than in catatonic or hebephrenic schizophrenia.[103] Another study demonstrated a substantially higher response rate for clozapine-ECT combination than clozapine alone after 8 weeks of combination therapy. However this was a single-blind study, and long-term efficacy was not measured.[104]

ECT has short-term efficacy [105],[106] and is safe in augmentation of clozapine in Schizophrenia with the predominant side effects reported to be nausea, tachycardia, hypertension, memory problems, and confusion.[106] There have also been reports of prolonged seizures during ECT and supraventricular tachycardia.[107] While an estimated 67% have been deemed to have “benefitted” from treatment,[106] there is little evidence that the reduction in relapse rates and symptomatic improvement in the short-term is maintained over the long-term.[108],[109] In addition, the highly variable number of ECT sessions used in various studies (ranging from 2 to 20 sessions), has made an evaluation of benefit difficult.

Nonpharmacological interventions

Smoking cessation

Poly-aromatic hydrocarbons found in cigarette smoke may induce the CYP1A2 enzyme system and reduce clozapine levels, by an estimated 34%.[110] The same study found that the majority (75%) of patients who did not reach therapeutic clozapine levels were smokers. It is unclear from available data, the amount of daily cigarette usage necessary for such an effect, but it is best, especially given the adverse cardiovascular effects of both clozapine and smoking, for the latter to be halted completely.

Occupational therapy

Individuals on clozapine who underwent regular occupational therapy sessions, either alone or in a group, were shown to have improved engageability and social skills, with a postulated “improvement in executive function,” over a period of 6 months.[111] It is possible that by equipping individuals with vocational and social skills imperative to independent living, chronic schizophrenia sufferers will adjust more easily once out of relapse.

Family therapy

High expressed emotion, in particular, critical comments by family members and extraverted personality traits in relatives, has been shown to increase relapse rates of individuals with chronic schizophrenia.[112] Methods to reduce expressed emotion via family interventions could be of benefit. Single Family interventions, where the therapist meets the family alone, have been shown to be most effective, compared to other forms of family therapy, in preventing relapse and improving medication compliance.[113] However, no trials have been done in conjunction with clozapine to date.

Alternatives to clozapine

Kerwin et al. recommend substitution with pharmacological alternatives to clozapine, in the event of nonresponse to clozapine,[114] and for the use of ECT once this step fails. In this regard, the use of risperidone and olanzapine as alternatives to clozapine has been best studied.

Bondolfi et al. demonstrated equal efficacy between risperidone at 6.4 mg/day and clozapine at 291 mg/day, with risperidone demonstrating a faster onset of action.[115] However, this result was not borne out in a comparative study that up-titrated the two drugs more slowly (over 8 weeks to a mean risperidone dose of 9 mg/day versus the 1 week period of the bondolfi study), which found that clozapine resulted in better CGI and BPRS scores at the end of the study period.[116] Brier et al. found that clozapine was superior to risperidone in alleviating positive symptoms, and caused less extrapyramidal side effects in the process though there was a little comparative benefit in negative symptom improvement.[117]

Olanzapine, which is the most commonly used “alternative” to clozapine,[118] has been shown to have comparative efficacy to clozapine with lower discontinuation rates due to adverse effects.[119],[120] There is also comparative efficacy and a good safety profile for olanzapine usage in patients who had previously been on clozapine but had stopped treatment due to nonresponse or adverse side effects (e.g., agranulocytosis).[121] Cognitive improvement has also been suggested to occur in individuals who are switched from clozapine to olanzapine.[122] However in individuals with early-onset schizophrenia, clozapine has been shown to be superior to olanzapine, with reduction of positive and negative symptoms at the end of the treatment trial.[123],[124]


The predominant problem in evaluating available literature is the lack of standardization between papers in determining, first, the duration of an adequate trial of clozapine, and secondly, what constitutes actual treatment resistance. Most trials recommend 3–6 months period of clozapine monotherapy, with one critical review suggesting a trial period of 12 weeks at serum levels of 350–420 ng/ml to ascertain if the response is likely.[125] Kontaxakis et al. found that only a minority of trials utilized clozapine at the appropriate serum level for the recommended duration, a salient point that we also noted in our review. Evidence also points toward a delayed therapeutic response to clozapine in a sizeable minority, with 10–20% of individuals responding only after 6 months duration of treatment, 50% manifesting response before that, and 30% not showing any improvement at all.[125]

Second, there was also little mention of the method of assessment of clinical status at the end of the trial with clozapine monotherapy. The commonly used measure is a 20% reduction in BPRS or PANSS scores [126] although this was often not mentioned in the evaluated papers, as was the discrimination between complete nonresponse, and partial response. It is possible that those who manifest a 10% improvement in BPRS/PANSS scores may form a different group from those who show a 0–5% improvement, and could require different strategies to achieve satisfactory response. To date, these heterogeneous categories have been classed under a single heading of “nonresponders.”

Another important consideration that needs to be looked for is concomitant substance abuse, which is estimated to occur in 60% of individuals in the West with chronic schizophrenia.[127] Substance use is itself associated with noncompliance to antipsychotics.[128]

Every augmentation strategy entails a cost, whether it is an additional monetary cost, adverse effects or greater stress to caregivers. The cost/benefit equation should be thoroughly evaluated and discussed before commencing a strategy. It may also be of value for a second opinion, preferably by a psychiatrist not involved in care, to evaluate the entire treatment history to date.

Given the multifaceted nature of schizophrenia, it is prudent to identify a target area for augmentation. Four target areas could be:

Positive symptomsNegative symptoms General symptoms, cognition, and social adjustmentImproved clozapine side effect profile.

Based on our review, the following strategies have been shown to be of benefit in each category.

Positive symptoms

Risperidone, amisulpride, sulpiride, haloperidol, aripiprazole (mild), lamotrigine, lithium (schizoaffective only), raloxifene, omega-3-fatty acids, memantine, ECT.

Negative symptoms

Amisulpride, sulpiride, aripiprazole, mirtazapine, gingko, memantine.

Cognition and social adjustment

Citalopram, lamotrigine (anti-aggression), topiramate, valproic acid, CX516, donepezil, occupational therapy.

Improved clozapine side effect profile

Amisulpride, fluvoxamine, topiramate, valproic acid, and omega-3-fatty acids. We would recommend starting with a strategy to reduce the clozapine side effect profile in patients who could potentially be noncompliant. Once satisfactory serum levels are achieved, the approach should be tailored to the patient's deficits, with a full discussion of potential adverse effects before augmentation.

Finally, the treating team should apply to their treatment targets a dose of realism. Schizophrenia is a chronic mental health condition and is often associated with progressive functional deterioration. Patients with clozapine resistance very often have had the condition for years, with many episodes of institutionalization in between. Thus, a complete functional recovery may not be achievable, and attempts to achieve it by the above methods may sometimes do more harm than good.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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