Why Choose Clozapine First for Schizophrenia

By Robert S. Laitman, MD
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Schizophrenia is a complex genetic condition that presents as a neurodevelopmental and, far too often, neurodegenerative disease. It is a spectrum of disorders that, without treatment, results in a chronic psychotic state in most individuals. 

Schizophrenia needs to be reclassified for what it is, a neurological syndrome. A better term to describe this varied condition is psychotic spectrum disorder. We are already aware of 108 genes that will increase the risk of developing schizophrenia. In families with these genes, clusters of other mental illnesses such as attention deficit hyperactivity disorder (ADHD) are also common. These individuals may have been spared some of the genetic risk or were not subjected to other stressors in life from conception onward (trauma, infections, drugs) that turn on at-risk genes (epigenetics) that would cause the full expression of schizophrenia. 

My immediate family is an example of how stressors may affect gene expression. My grandfather and uncle had schizophrenia, and my aunt struggled with bipolar I disorder with psychosis. I had an idyllic upbringing with an ACE (Adverse Childhood Experiences) score of 0 and arguably was relatively spared. Yet my son, also with an ACE score of 0, was subjected to an in-utero trauma of gestational diabetes and developed schizophrenia.   

Schizophrenia can be considered primarily a disease of gating. Gating is the ability of an individual to focus attention on a task while tuning out extraneous internal and external stimuli. People with schizophrenia frequently do not gate well and are therefore continuously flooded by stimuli. Even early in life, many people who eventually develop schizophrenia are much less social and have attention deficit disorders. No matter how hard they try, their minds remain jumbled. With this “unquiet mind,” they are increasingly stressed, resulting in inappropriate limbic activation. As further neurodevelopment occurs, especially during adolescence, this entire process accelerates as synaptic pruning (the brain’s natural removal of unneeded connections) occurs. The ability to gate worsens, and stress accrues. 

Further limbic activation, (the limbic regions of the brain regulate emotional responses) driven by dopamine, occurs and, with this, symptoms of hallucinations and delusions become prominent. As gating continues to diminish, negative symptoms such as lack of motivation and social isolation appear, and cognition declines. All this leads to a “break” from reality. Often during this time, patients begin smoking cigarettes in an attempt to self-medicate and improve gating. Others try to quiet their minds with marijuana, which unfortunately, in these susceptible individuals, further exacerbates the psychosis. 

Schizophrenia, therefore, needs to be thought of as a disease that often starts before birth. For example, one primary risk gene encodes the alpha-7 nicotinic receptor. This receptor system in utero is responsible for the full neurodevelopment of the brain’s “operating systems.” After birth, this receptor is positioned on inhibitory interneurons that are responsible for turning on and off sensory neurons. This process is a critical component of the gating mechanism. As sensory input comes in from a variety of sources, interneurons will shut down neurons that are processing the extraneous while turning on neuronal pathways that allow for focused attention. In patients with schizophrenia, this receptor system is not fully developed. From an early age, these children will often experience social anxiety, attention deficit, and other behavioral issues. 

Not everyone with this gene develops schizophrenia. However, if these same individuals early in life are subjected to physical or emotional trauma from in utero (e.g., infection, drug abuse, starvation) to childhood physical or psychosocial stressors, there is a propensity for epigenetic triggers to give full expression to the illness. Even in individuals without obvious stressors, the illness may come to fruition. For instance, this can occur if they have another gene that results in overabundant synaptic pruning.

Synaptic pruning is a normal stage of development during adolescence and ideally would rid the brain of neural pathways that are redundant or harmful and strengthen “good” pathways. This gene is responsible for the expression of complement. Complement is part of the immune system that enhances the ability of antibodies and immune cells to clear microbes and damaged cells from an organism. It also promotes inflammation. When this gene is overexpressed, too much complement deposits on neurons, resulting in the microglia destroying or pruning these cells. The pruning is often most extreme in the prefrontal cortex, where most executive functioning occurs. In the general population, this gene by itself increases the risk of developing schizophrenia by 25 percent.1 Essentially these individuals were dealt an unfair hand. 

The pathophysiology of schizophrenia spectrum disorders provides a format for a reasoned approach to treatment. We need to start at the beginning. We know that choline supplementation in pregnancy appears to improve the outcome of children who are at high risk of mental illness. Supplemented children have reduced rates of ADHD and social isolation in the first four years of their lives.2 The hope is that these children will have a reduced risk of developing schizophrenia. In rats, it has been shown that choline supplementation increases the expression of alpha-7 nicotinic receptors. This results in normalizing neurodevelopment and normal gating. Four grams, twice a day of Lecithin (phosphatidylcholine) should become a routine prenatal supplement. Once the child is born, attempts should be made to reduce possible epigenetic triggers. Inflammation is one of these triggers. For this reason, fish oil has been proposed as an early supplement in at-risk individuals. One gram of fish oil is innocuous and something that McGorry has demonstrated to decrease the progression of the prodromal syndrome to a schizophrenia syndrome.3

Finally, early intervention in psychosis is critical. Inciting agents that are known to increase the risk of developing psychosis, such as stimulants and cannabis, should be eliminated. And, agents that are effective at attenuating the syndrome should be used as early as possible. Clozapine, for this reason, should be used at the inception of illness. Not only is it the most effective agent, it is the only agent that has direct effects on the microglia and blocks the overabundant synaptic pruning. Finally, clozapine has been shown to effectively restore alpha-7 nicotinic receptors at the interneurons. This leads to improved gating and continued improvement.4 


Why clozapine first? 

The initial response to any and all antipsychotics for initial treatment is reported to be anywhere from as low as 40 percent to as high as 70 percent. When a patient with schizophrenia does not respond initially and requires a second antipsychotic, not including clozapine, the response rate is seven percent, and usually, this is only a partial response. However, when this same refractory patient is given clozapine, the eventual response has been reported to be 50 to 70 percent.5 My results have been even better than this. A response to clozapine can be delayed for over one year, so it is important not to give up prematurely. The current guidelines have clozapine as only a third-line agent. There is now enough clinical evidence to move clozapine up to a second-line agent at the very least. My contention is that it should be the first agent used.


Is clozapine the best choice as a first-line agent? 

Clozapine has shown advantages over other typical and atypical antipsychotics clinically, neuropsychologically, and socially. Clozapine contributes to the improvement of positive, negative, affective and cognitive symptoms in addition to reducing drug abuse, aggressive behavior by 38 percent when compared to Olanzapine and Haldol, and suicide attempts by 84 percent when compared to typical antipsychotics and 25 percent with Olanzapine.6 It is superior in terms of therapeutic adherence,7 quality of life, self-perceived satisfaction with treatment, and overall survival.8,9,10 Furthermore, clozapine is generic and, despite the stringent monitoring required, has been demonstrated to be the most cost-effective antipsychotic. Special emphasis on early intervention is critical to stop clinical, neuropsychological, neurophysiological, and neurostructural decline. Effective treatment using pharmacology, psychotherapeutic modalities, and psychosocial support needs to be the standard. A global supportive approach can change the trajectory of the illness and often restore function to the premorbid state. In the RAISE trial, they found that early effective treatment in the first 18 months of the illness resulted in the best outcome.11 However, even in this population, the longer the duration of untreated psychosis, the worse the outcome. Further support of this was provided by Yoshimura in 2017.12 They demonstrated a critical treatment window for clozapine treatment of resistant schizophrenia. Treatment after 2.8 years of known disease did not yield nearly as good outcomes as earlier treatment.13

In the 2017 Schizophrenia Bulletin, Schoenbaum reported the 12-month mortality in commercially insured young people with incident psychosis in the United States.14 It is an astounding 24 times greater than the general United States population aged 16 to 30. We know that most of this excess mortality is from suicide, violence, and concomitant drug abuse. Clozapine has unique beneficial effects in all domains. We are failing these individuals, as clozapine use in this setting in the first year is presently nil. 

Another critical analysis supporting this argument was published in JAMA Psychiatry and authored by Tiihonen. He looked at the real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29,823 patients with schizophrenia. Of these, 4,603 were newly diagnosed. In Sweden, prospectively gathered national databases were linked to study the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients with schizophrenia from age 16 to 64 years in 2006. Clozapine and long-acting injectable (LAI) antipsychotic medications were the pharmacologic treatments with the highest relapse prevention rates. The risk of rehospitalization was 20 to 30 percent lower for those patients treated with clozapine or long acting injectables (LAIs) overall. The lowest rate of treatment failure was observed for clozapine with the LAIs in a distant second place. All other oral antipsychotics outside of clozapine were inferior in their efficacy.15 

Given all of the overwhelming data of clozapine’s clear superiority in all settings,16 I believe that using clozapine at the debut of the disease gives the patient suffering from schizophrenia the best chance for success. Resistant schizophrenia was merely a “big pharma” construct to extend a patent giving clozapine a new drug indication. It is time that this far too often devastating illness is given the appropriate early aggressive treatment required to get the best outcomes.
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1) Freedman, R., and R. G. Ross. “Prenatal Choline and the Development of Schizophrenia.” Shanghai Archives of Psychiatry , vol. 27, 2015, pp. 90–102.
​2) Freedman, Robert, et al. “Higher Gestational Choline Levels in Maternal Infection Are Protective for Infant Brain Development.” The Journal of Pediatrics, vol. 208, 2019, pp. 198–206., doi:10.1016/j.jpeds.2018.12.010.
​3) McGorry, Patrick D, et al. “Early Intervention in Psychotic Disorders: Detection and Treatment of the First Episode and the Critical Early Stages.” Medical Journal of Australia, vol. 187, no. S7, 2007, doi:10.5694/j.1326-5377.2007.tb01327.x.
4) Opler, Lewis A., and Robert Laitman. Meaningful Recovery from Schizophrenia and Serious Mental Illness with Clozapine: Hope & Help. 4th ed., 2017.
​5) Stahl, Stephen M., and Jonathan M. Meyer. The Clozapine Handbook. Cambridge University Press, 2020.
​6) Meltzer, Herbert Y. “Clozapine Treatment for Suicidality in Schizophrenia: International Suicide Prevention Trial (Intersept).” Archives of General Psychiatry, vol. 60, no. 1, 2003, p. 82., doi:10.1001/archpsyc.60.1.82.
​7) Lieberman, Jeffrey A., et al. “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia.” New England Journal of Medicine, vol. 353, no. 12, 2005, pp. 1209–1223., doi:10.1056/nejmoa051688.
8) Meltzer, Herbert Y. “Clozapine.” Clinical Schizophrenia & Related Psychoses, vol. 6, no. 3, 2012, pp. 134–144., doi:10.3371/csrp.6.3.5.
​9) Taipale, Heidi, et al. “20‐Year Follow‐up Study of Physical Morbidity and Mortality in Relationship to Antipsychotic Treatment in a Nationwide Cohort of 62,250 Patients with Schizophrenia (FIN20).” World Psychiatry, vol. 19, no. 1, 2020, pp. 61–68., doi:10.1002/wps.20699.
​10) Tiihonen, Jari, et al. “11-Year Follow-up of Mortality in Patients with Schizophrenia: A Population-based Cohort Study (Fin11 Study).” The Lancet, vol. 374, no. 9690, 2009, pp. 620–627., doi:10.1016/s0140-6736(09)60742-x.
​11) Kane, John M., et al. “Comprehensive versus Usual Community Care for First-Episode Psychosis: 2-YEAR Outcomes from the NIMH Raise Early Treatment Program.” American Journal of Psychiatry, vol. 173, no. 4, 2016, pp. 362–372., doi:10.1176/appi.ajp.2015.15050632.
​12) Yoshimura, Bunta, et al. “The Critical Treatment Window of Clozapine in Treatment-Resistant Schizophrenia: Secondary Analysis of an Observational Study.” Psychiatry Research, vol. 250, 2017, pp. 65–70., doi:10.1016/j.psychres.2017.01.064.
​13) Stahl, Stephen M., and Jonathan M. Meyer. The Clozapine Handbook. Cambridge University  Press, 2020.
​14) Schoenbaum, Michael, et al. “Twelve-Month Health Care Use and Mortality in Commercially Insured Young People with Incident Psychosis in the United States.” Schizophrenia Bulletin, vol. 43, no. 6, 2017, pp. 1262–1272., doi:10.1093/schbul/sbx009.
​15) Tiihonen, Jari, et al. “Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients with Schizophrenia.” JAMA Psychiatry, vol. 74, no. 7, 2017, p. 686., doi:10.1001/jamapsychiatry.2017.1322.
​16) Vermeulen, Jentien M, et al. “Clozapine and Long-Term Mortality Risk in Patients with Schizophrenia: A Systematic Review and Meta-Analysis of Studies Lasting 1.1–12.5 Years.” Schizophrenia Bulletin, vol. 45, no. 2, 2019, pp. 315–329., doi:10.1093/schbul/sby052.