Clozapine Augmentation in Clozapine Resistant Schizophrenia – Quick Review – 2023 Update

CLOZAPINE IN TREATMENT RESISTANT SCHIZOPHRENIA

Clozapine is an evidence-based treatment in TRS.

A recent meta-analysis concluded:

Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13–0.56) and non-TRS (g = 0.20; 95%CI, 0.08–0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. These findings do not support a subtype of schizophrenia which respond specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia. [Mizuno et al, 2019]

There is evidence that clozapine initiation is delayed in clinical practice, and early treatment with clozapine in TRS is associated with better outcomes.

Clozapine treatment is associated with positive outcomes: 

• Reduces positive symptom scores (Positive and Negative Syndrome Scale; PANSS)
• Reduces suicidal risk
• Reduces aggressive behaviours
• Reduces hospitalization rates
• Improves overall mortality rates

Read more on

Mechanism of action of clozapine

Optimising Drug Treatment for Psychosis: Using What We’ve got Better – Role of Clozapine.

Clozapine Anti- Suicidal effect 

CLOZAPINE RESISTANCE

Up to 40% of patients do not respond to clozapine treatment, and up to 70% of patients will only exhibit a partial or limited response. A partial response criterion is quantified as only a 20-30% reduction in Brief Psychiatric Rating Scores (BPRS) or PANSS scores [Porcelli et al. 2012].

Delay in the initiation of clozapine is associated with a poorer response to clozapine, raising the possibility of a critical period for initiation (2.8 years). [Yoshimura et al., 2017]

Clozapine resistance occurs despite a dosage of 300 to 800 mg/day, with blood tests revealing adequate plasma drug levels of 350 to 420 ng/mL.

Some studies have suggested that there are late responders and that a period of 3 to 6 months is necessary [Rosenheck et al. 1999]; however, others have rejected the delayed-onset hypothesis.  [Agid et al. 2003]

However, the criteria for clozapine-resistant schizophrenia have been defined [Mouaffak et al. 2006]:

• Less than 20% improvement in BPRS after ≥8 weeks of clozapine therapy despite plasma levels >350 μg/L.
• BPRS total score of ≥45.
• Global assessment of functioning score of ≤40.
• CGI score ≥4.
• A period of ≥5 years, where the patient has not had a stable social and/or occupational function.

Although there are notable barriers to treatment with clozapine, the co-prescription rates in Australia were reported to be as much as 85% in 2012—this suggests that clinicians show a reasonably aggressive tendency to augment clozapine in patients that exhibit signs of clozapine-resistant schizophrenia.[Pai et al. 2012]

The study included benzodiazepines, anti-metabolic agents and anticholinergic, which may be prescribed for side effects rather than a true pharmacological augmentation for enhancing clozapine efficacy.

CLOZAPINE AUGMENTATION STRATEGIES - THE EVIDENCE

A recent Finnish study showed that Antipsychotic polypharmacy (APP) may be associated with significantly lower psychiatric hospitalisation risk due to any psychiatric and nonpsychiatric reasons and may also reduce mortality more than treatment with antipsychotic monotherapy. [Tiihonen et al., 2019]

In principle, when considering combining antipsychotics, it would make the most sense to combine agents with different pharmacodynamic dopamine actions, such as combining a full antagonist with a partial agonist, or a tight D₂ binding agent with one with less potent D₂ binding (such as quetiapine or clozapine). [Guinart and Correll, 2020]

See this interview with Prof Correll on the augmentation of Lurasidone and Clozapine. 

Prof Bloom talking about strategies for non-responders with Clozapine. 

Similarly, combined antipsychotics should not double up on the same dopaminergic and/or extradopaminergic activity and related adverse effects (s), including sedation, insomnia, weight gain, Parkinsonism, akathisia, prolactin elevation, and QTc prolongation. Rather, antipsychotics with complementary adverse effect profiles should preferentially be combined.

A 2016 review outlined the following augmentation strategies in clozapine resistant schizophrenia [Kudva and Gupta, 2016]:

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 (allows for the reduction in dose of clozapine and reduced hypersalivation)
• Fluvoxamine (improved metabolic profile)
• Topiramate (reduced Weight gain)
• Valproic acid (reduced weight gain)
• Omega 3 fatty acids (reduced triglyceride levels)

Non-pharmacological options:

• Gingko (effective on negative symptoms with little effect on positive symptoms)
• Smoking cessation:

Smokers were less likely to reach therapeutic levels. Smoking cessation may benefit by counteracting the cardiovascular risks and pharmacokinetic interactions with polyaromatic hydrocarbons.

Impact of Smoking on Clozapine Levels – Management of Smoking Cessation in Clozapine Treatment

• Occupational therapy

Individuals on clozapine who underwent regular occupational therapy sessions, either alone or in a group, were shown to have improved social skills, with a postulated “improvement in executive function” over a period of 6 months.

• Family therapy

Benefits in relapse prevention and improving compliance

EVIDENCE FOR CLOZAPINE AUGMENTATION STRATEGIES FROM A META-REVIEW

Wagner and colleagues recently published a meta-review that outlined a clinical strategy to treat clozapine-resistant schizophrenia using The Scottish Intercollegiate Guidelines Network (SIGN) [Wagner et al. 2019]. SIGN was formed in 1993 and was designed to reduce variation in clinical practice.

This meta-review included 21 publications on clozapine resistance, and each publication was reviewed using the SIGN criteria to determine scientific validity prior to grading (Grade A-D): (Read more about grading criteria)

Grade B:

First Generation or Second Generation Antipsychotics (FGA or SGA)

• Clozapine combination with an FGA or an SGA was previously reported as significantly superior to monotherapy, although this result was not reproducible when only including high-quality studies. [Galling et al. 2017]
• When choosing a combination strategy, it has been reported that amisulpride (positive and negative symptoms), aripiprazole (negative symptoms; > 24 wks study for positive symptoms), or risperidone (positive symptoms) were favourable combinations. [Kudva and Gupta 2016]

Antidepressants:

• Although no direct effect, the benefits of augmentation with antidepressants primarily include their inherent antidepressant effect, which may assist in social rehabilitation. [Correll et al. 2017]
• Also, SSRIs inhibit the hepatic CYP enzyme system, which metabolises clozapine (paroxetine increases clozapine levels by 31%). [Bertilsson et al 1994]; [Spina et al 2000].
• Fluvoxamine inhibits CYP1A2,  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. [Kudva and Gupta 2016]
• Clozapine can worsen OCD symptoms, and SSRIs may reduce this. [Kudva and Gupta 2016]
• A recent systematic review concluded that compared to other treatment strategies, clozapine non-responsive patients respond maximum to mirtazapine followed by ECT. [Grover, 2023].

ECT:

• Clozapine augmentation with ECT increases blood-brain barrier permeability and therefore, may increase the levels of clozapine reaching the brain, although this benefit is only short-term.
• Response rates across several trials were reported to be between 54% and 66%, and therefore augmentation with ECT represents an effective add-on strategy; however, there are concerns of an increase in side effects [Lally et al. 2016]

Grade C:

Mood Stabilisers

Lithium

Lithium is a proven mood stabiliser that may also reduce the incidence of clozapine-induced neutropenia. Clozapine augmentation with lithium has been shown to significantly improve total and positive symptoms but not for negative symptoms. [Siskind et al. 2018]

• In contrast, schizoaffective patients may benefit from mood stabilisers with improvements in negative and cognitive domains [Small et al. 2003].

Lamotrigine

Improvement in global scores and reduced verbal aggression as an augmentation agent.

Valproate

• Valproate is currently indicated for prophylaxis against seizures in patients on high doses of clozapine. Valproate has been hypothesised to modulate 5HT2A receptor activity [Kurita et al. 2013], and augmentation with clozapine is significantly superior to clozapine monotherapy.  [Zheng et al 2017]; [Siskind et al 2018]

Topiramate

Not been found to confer any superiority as an augmentation strategy [Correll et al. 2017].

Carbamazepine:

• Avoid carbamazepine due to the risk of agranulocytosis (synergistic effect of bone marrow suppression).

rTMS

Repetitive transcranial magnetic stimulation (rTMS) utilises a low-frequency magnetic field to stimulate the left temporoparietal region, reduce the severity of auditory hallucinations, and show evidence in resistant schizophrenia.

Augmentation with rTMS requires more research as there is a lack of high-quality RCTs. Only one pilot trial has shown that there were improvements in general psychopathology in clozapine resistant schizophrenia. [de Jesus et al. 2011]

A meta-analysis showed no benefit of rTMS for psychotic symptoms in clozapine refractory patients. [Siskind et al., 2019]

Grade D:

Glutamatergic agents (e.g. glycine, D-cycloserine, and CX516)

• Augmentation with glutamatergic agents such as glycine, D-cycloserine, and CX516 is considered due to the hypo-glutamatergic hypothesis of schizophrenia. This hypothesis postulates that NMDA receptor inactivity is responsible for the negative symptoms of schizophrenia. Although the evidence supports a role for glutamate, most data on cases of clozapine-resistant schizophrenia are inconsistent [Sommer et al. 2012]; [Correll et al. 2017]; [Siskind et al. 2018]

CBT

• Cognitive behavioural therapy (CBT) has previously been shown to reduce emotional distress and anxiety in patients with schizophrenia. [Pontillo et al. 2016]
• However, studies into clozapine augmentation with CBT are scarce with only a single trial in 2009 showing that CBT did not improve positive or negative symptom scores in clozapine-resistant schizophrenia. [Barretto et al. 2009]

Transcranial direct current stimulation (tDCS) :

• Case report evidence currently – more evidence needed.

CONCLUSION

Treatment resistance and inadequate response to clozapine treatment is a considerable clinical problem for a significant proportion of TRS patients. The disparity between clinical practice and recommended guidelines has resulted in uncertainty in the appropriate strategy to augment clozapine therapy.

According to the RANZCP guidelines –

Clozapine has had some – even modest – benefit, augmentation is justifiable, although the evidence for this strategy is equivocal. On an individual level, the addition of a high affinity dopamine D2 blocking agent such as risperidone or amisulpride to clozapine can be effective for residual positive symptoms. [RANZCP guidelines in Schziophrenia] 

The current body of evidence doesn’t endorse any single approach and instead argues that any combination or augmentation trial should be systematically researched a priori and incorporate the unique cost-benefit ratio for each patient.

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