Clozapine remains the golden standard for patients with treatment-resistant schizophrenia. Despite decades of research, a successor has not so far been found. In this edition, Siskind et al.1 published a systematic review on plasma levels of clozapine and reached the conclusion that psychiatrists should target clozapine levels above 350 ng/ml before augmentation should be considered. This is an important finding and an important piece in a puzzle containing many pieces.

With this editorial, I would like to put this finding in a wider context. Clozapine is worldwide licensed for treatment-resistant schizophrenia (TRS), and most guidelines agree that TRS should be defined as inadequate response to at least two antipsychotic drugs and clozapine should be offered at that time.2 Timing of clozapine initiation is important as treatment with clozapine is associated with the risk of serious adverse effects, such as agranulocytosis and myocarditis, and consequently, clozapine should not be used if response can be achieved using a drug with a safer adverse effect profile. On the contrary, delaying clozapine initiation has been associated with a reduced chance of response.3 Whether clozapine overall is a more effective antipsychotic drug than non-clozapine antipsychotics or only more effective in TRS have been debated.4 Regardless of the answer to that question, sledgehammers should not be used for cracking nuts.

The criterium of inadequate response to at least two antipsychotic drugs seems easy to understand, but in clinical practice, it may be more difficult to comply with, as several factors should be taken into consideration. In order to achieve response to an antipsychotic drug, adequate dose and treatment duration are essential. According to the Treatment Response and Resistance in Psychosis (TRRIP) guidelines, the duration of antipsychotic treatment should at least be 6 weeks and the dose should at least be the midpoint of the dose range stated in the summary of product characteristics.5 Only treatment episodes where adequate dose and duration have been reached should be included in the clozapine eligibility criterium. However, reaching adequate dose may be complicated by adverse effects, especially in patients with first episode psychosis as they are more prone to develop adverse effects. Consequently, these patients may need more trials of antipsychotics before they are eligible for clozapine because inadequate response cannot be determined. Paradoxically, later in the course the patient may have developed less vulnerability to adverse effects and may then tolerate the sufficient dose needed in the clozapine eligibility criteria. However, at that time point the chances of response might have decreased as treatment resistance may have developed. Unfortunately, number of previous trials due to tolerability and numbers due to lack of efficacy are rarely specified in research trials involving clozapine neither.

Often, treatment response is evaluated retrospectively based on hospital records, which often lead the current treating psychiatrist in a situation where essential information is missing. Using psychopathology, rating scales, such as Positive and Negative Syndrome Scale (PANSS), are rarely used routinely in clinical practice. Even though a rating scale is used, the symptoms measured are depending on the willingness of the patient to share information about their situation, the interaction between the patient and the interviewer, and the interviewer's interpretation of the provided information. In addition, the interview is only a snapshot of the clinical state and may not be representative of the treatment episode. Psychiatric symptoms, such as hallucinations, are subjective as pain; consequently, patients may on a good day use more coping strategies diminishing the level of psychiatric symptoms reported compared to the level reported on a “rainy” day.6 These challenges make it important to conduct several interviews and include reporting from relatives and care persons.

Another important factor is compliance to antipsychotic treatment, as response cannot be achieved if the patient is not taking the drug. This is called pseudo-resistance, and these treatment episodes should not be counted in the criteria for being clozapine eligible. Unfortunately, it is difficult to estimate compliance of oral treatment.

The need for antipsychotic treatment is not static but dynamic and influenced by inner and outer conditions, such as stress level, living conditions, somatic comorbidity, course of the disease, previous episodes, substance abuse, and general well-being. Current clinical state must be the result of factors that aggravate and improve psychiatric symptoms. Consequently, patients may respond to a specific drug or a specific dose at a certain time period of their life, whereas there is different need for antipsychotic treatment in other time periods. These considerations are often neglected in a research context as the influencing factors are difficult to measure. Hopefully, future research can shed more light on these circumstances as many clinically relevant questions about response remain unanswered.

Another intriguing factor is the kind of symptoms we include in the response criteria. Most psychiatrists tend to put their focus on treating positive symptoms, such as hallucination and delusions, whereas the level of social functioning and quality of life of many patients would be improved more through an improvement of negative symptoms.7 The focus of the treatment should be included in the process of when clozapine is the right drug of choice.

All these circumstances add to the complexity of counting to two antipsychotic treatment episodes with inadequate response and deciding when to prescribe clozapine is more than just counting to two. The process warrants close evaluation of previous treatment episodes, current symptomatology, and the involvement of the patient and the relatives.

Now, let us move on to the prescribing of clozapine. When initiating clozapine, the titration speed should be determined as a balance between the need for rapid symptom control and the burden of dose-dependent adverse effects. Many of the adverse effects of clozapine diminish over time as a result of tachyphylaxis. The concentration/dose (C/D) ratio plays an important role in deciding the titration speed and the target dose. As a large inter-individual variation in C/D ratio exists, therapeutic drug monitoring (TDM) is an essential tool in clinical decision-making when titrating clozapine.8

The first months of treatment is a critical time period as the patients experience more adverse effects, and the treatment has not fully been optimized. Maintaining patients on clozapine during this time period is of high importance as the potential of clozapine has not been determined yet. In addition, most serious adverse effects occur during the first months of treatment. Often, agranulocytosis is in focus, but inflammatory conditions, such as myocarditis, are more often having a fatal outcome.9 Constipation remains a dangerous adverse effect with a potential fatal outcome and should be monitored during the entire period treating with clozapine.10

In the maintenance treatment, the metabolic adverse effects become significant with increasing body weight and cardiovascular risk factors.11 Despite the metabolic burden can seem overwhelming, it is important to remember that treatment with statins and hypoglycemics also reduce mortality in this patient group.12 Despite the metabolic burden and the potentially fatal adverse effects, epidemiological studies find that continuous clozapine treatment is associated with lower overall mortality compared to other antipsychotics.13

In case of insufficient response, dose optimization of clozapine is essential. Higher doses can sometimes better be tolerated if the total dose is split several times during the day, especially, if that makes withdrawal of other psychotropics feasible, such as benzodiazepines. Optimization of the dose is the first step, and, as Siskind et al. states, it comes before considering augmentation.

In the process of optimization, it is important to involve the patient and follow what is most important for the patient; for example, negative symptoms may be aggravated by too high doses of antipsychotics. Many patients are more interested in having the burden of adverse effects reduced. This can sometimes be done by augmentation too, by using a clozapine sparing antipsychotic drug that facilitate clozapine dose reduction. Unfortunately, not much evidence is supporting this practice.

As years go by on clozapine, many patients have the desire to reduce the dose or discontinue clozapine, and some patients may manage their disease with reduced dose of clozapine or without clozapine. No doubt that standard dose of antipsychotics offers better protection against psychotic relapse,14 but treatment for schizophrenia is more than just preventing relapse.

With the complexity mentioned above, how do we identify patients eligible for a gradual tapering of clozapine? Interestingly, we tend to focus on the current level of symptoms whether we are recommending tapering of clozapine; per se tapering of clozapine is rarely performed in patients with active symptomatology, even though the entire daily dose of clozapine may not contribute positively to the current clinical state. We, psychiatrists, should remember the fact that many patients are willing to trade a dose reduction, and thereby less adverse effects, for a slight increase in symptoms. Another factor to remember is that most of the adverse effects affecting quality of life, such as sedation, orthostatism, and hypersalivation, are dose-dependent adverse effects and even a small dose reduction may improve the condition.8 Unfortunately, most research about life beyond clozapine stems from patients discontinuing clozapine abruptly, for example, due to serious adverse effects or because the patients decided to discontinue clozapine on their own.15 The latter might be the consequence of not being met in their request of gradual dose reduction. More studies investigating which patients that safely can have their clozapine dose reduced and to which degree are warranted.

So far, many clinically relevant questions remain unanswered. Until then, let us admire the complexity of psychiatry and the use of clozapine.