Antipsychotic Misadventures

The term antipsychotic, in my view, is archaic and misleading. In the early years of treating individuals with schizophrenia with medications, a variety of other terms were used interchangeably to describe this class, most notably major tranquilizers and neuroleptics.¹ Beginning with my medical/psychiatric internship in 1986, and throughout my 40 years of practicing psychopharmacology, I have learned a great deal about the consequences of antagonizing the brain’s dopamine D2 receptors (D2Rs). The cases reported here are based on my treatment of patients diagnosed with schizophrenia with D2R antagonists.

Historical Context

Let’s begin with a historical overview. The year 1954 marked a paradigm shift for the treatment of schizophrenia when chlorpromazine was first used in the United States to improve symptoms of hallucinations, delusions, and agitation, or positive symptoms. Regrettably, what got lost with this novel treatment was the focus on the other 2 core symptoms in schizophrenia: cognitive and negative symptoms. In fact, the D2R antagonism of all antipsychotics—believed to be the mechanism to treat the positive symptoms—can worsen the negative and cognitive symptoms, which are often referred to as secondary negative symptoms² and are primarily related to progressive functional impairment in individuals with schizophrenia. Unsurprisingly, schizophrenia was initially called dementia praecox in the 1880s, a term popularized by Emil Kraepelin in the early 20th century. Between 1918 and 1952, the terms schizophrenia and dementia praecox were used interchangeably.

As is often the case with any medical treatment, there is a fine balance between the benefits of an antipsychotic and the various risks, or adverse events. With D2R antagonists, the benefits can be dramatic, significantly improving the positive symptoms that can be so debilitating and disabling in some patients. The adverse effects of ubiquitously antagonizing all of the D2Rs in the human brain include motor adverse effects (acute dystonic reaction, drug-induced parkinsonism, akathisia, tardive dyskinesia), hyperprolactinemia (gynecomastia, galactorrhea, breast tenderness, menstrual irregularity, decreased libido, decreased fertility, long-term risk of osteoporosis), cognitive impairment, sedation, weight gain, dysphoria, secondary negative symptoms, and others.

Case 1: “Increase the Dose Until They Have Cogwheeling”

During my residency training, one of my supervisors instructed me to treat inpatients with schizophrenia experiencing acute psychosis with an antipsychotic until the D2R blockade achieved cogwheeling, a symptom shared with Parkinson disease. This involves holding the patient’s hand and bending the arm at the elbow until the hand approaches the shoulder, and then bending the arm back to full extension. Cogwheeling feels like a ratcheting of the arm muscles as the arm is extended, a clinical effect well known by neurologists and psychiatrists alike. I was instructed that once I observed cogwheeling, I should lower the dose of the antipsychotic by approximately 20%, which would achieve the ideal occupancy to treat psychosis. In more recent years, this approach has been described as “a poor person’s PET scan.” The unfortunate reality of this approach to determining the clinically effective antipsychotic dose is that the patient experiences pseudoparkinsonism in the process, which is an adverse event that can hinder a patient’s motivation and willingness to take the antipsychotic.

Reflections

In the late 1980s, this clinical technique was consistent with what had been learned about the percentage of D2R binding required to achieve an antipsychotic effect vs causing motor adverse effects. In 1988, Farde et al demonstrated that 65% to 85% of D2Rs were occupied in patients with schizophrenia treated with clinical doses of 11 different antipsychotic medications, using PET imaging with the dopamine antagonist radioligand C¹¹ raclopride.³

Subsequent studies demonstrated that occupancy greater than 80% of D2Rs correlated with motor adverse effects.⁴ Collectively, the current paradigm suggests that D2R occupancy by an antipsychotic between 65% and 80% at maximum concentration (C_max) is the range for a good antipsychotic response with minimal motor adverse effects, and that occupancy above 80% predicts increasing motor adverse effects.⁵ Significantly, by the 1990s, PET D2R occupancy had become a standard tool in the development of antipsychotics. By 2000, the US Food and Drug Administration (FDA) expected PET D2R occupancy studies as part of an antipsychotic’s clinical development.

Why do we not use PET D2R occupancy clinically to determine the optimal dose of an antipsychotic in our patients? PET is routinely used in other disease states to assess many metrics, including the degree of pathology, treatment response, and relapse screening. In an ideal health care system with unlimited resources and ubiquitous access, PET scans to document D2R occupancy throughout the treatment of a patient with schizophrenia would be a welcome diagnostic tool. In our current health care system, due to high costs, limited access, and insurance noncoverage, we are unable to order a PET scan using the radioligand C¹¹ raclopride to determine the precise D2R occupancy of an antipsychotic in our patients.

The D2R therapeutic occupancy range of between 65% and 80% has long been accepted as the target range in drug development to maximize efficacy and minimize many adverse effects, including motor adverse effects and hyperprolactinemia. An exception to this is lumateperone (Caplyta), in which a study of patients with schizophrenia on lumateperone 42 mg/day for 14 days demonstrated 39% D2R occupancy at C_max.⁶ Various hypotheses have been presented to explain this outlier finding, and as predicted by the general model of D2R occupancy, lumateperone has virtually no motor adverse effects or increase in prolactin levels.

Case 2: “I Cannot Stop Vomiting”

In the fourth year of my psychiatry residency, I had been treating a 34-year-old man with chronic treatment-resistant schizophrenia for over a year when my supervisor and I discussed initiating a trial of the new antipsychotic clozapine (Clozaril), which had just been FDA approved. This man had not responded to several adequate trials of adequate doses of typical antipsychotic medications over the previous 10 years. He had been receiving perphenazine (Trilafon) 64 mg/day (the maximum dose) for the past year, with no significant improvement in his chronic paranoid delusions and hallucinations. Clozapine was initiated and steadily titrated to the target dose. After several weeks, the perphenazine was quickly tapered and discontinued over a week. One week after the full discontinuation of the perphenazine, the patient called me through our emergency services and reported intractable nausea and vomiting over the past 48 hours. I met him for an emergency appointment that day, and upon entering my office, he grabbed for the trash barrel and proceeded to vomit into it, clearly distressed. Having already consulted with my supervisor, I restarted the perphenazine at 32 mg/day, and within 8 hours, the nausea and vomiting had subsided. Continuing the upward titration of the clozapine to a therapeutic serum level, the perphenazine was slowly tapered by 4 mg/week until it was fully discontinued, with no recurring nausea or vomiting.

Reflections

Clozapine had just become available as our first atypical antipsychotic, and we had much to learn. In retrospect, the intractable nausea and vomiting were entirely predictable, as this patient had chronic antagonism of his central D2Rs for many years, which provided a constant antiemetic effect that had been rapidly removed with the fast titration down and off of the perphenazine. Clozapine has significantly weaker antagonism of the D2R, and as such, offers significantly less antiemetic effect. By 1928², it had been established that D2R antagonism effectively manages nausea and vomiting triggered by chemical stimuli, including medications, through the chemoreceptor trigger zone.⁷

This phenomenon is especially prescient today with the recent FDA approval of xanomeline and trospium chloride (Cobenfy), which is indicated for the treatment of adults with schizophrenia but lacks any D2R binding. Hence, rapidly cross-titrating a patient from a D2R antagonist to Cobenfy could increase nausea and vomiting, which are already reported as the initial adverse effects of Cobenfy.

Case 3: “Why Is the Patient on 3 Antipsychotics?”

During the past 18 years working at our community mental health center, I have performed many initial evaluations on patients referred to our clinic from an outside provider with the diagnosis of treatment-resistant schizophrenia. Not uncommonly, the patient presents on 3 antipsychotic medications, which reportedly were prescribed because the patient was not improving. It is a rare occasion when a plasma antipsychotic level of any of the 3 medications has been previously obtained, despite this being the standard of care for a nonresponder. An informative publication by McCutcheon et al measured plasma antipsychotic levels in 99 patients provisionally diagnosed by their clinicians as having treatment-resistant schizophrenia and not prescribed clozapine.⁸ The patients were then prospectively followed for the subsequent need for psychiatric hospitalization. In total, 35% of plasma levels were subtherapeutic, with 34% of these reporting the absence of any antipsychotic. Prospectively, these subgroups had a significantly higher likelihood of being psychiatrically hospitalized.

Often, there is a lack of a rational pharmacodynamic explanation as to why these 3 specific antipsychotics were prescribed together. Not uncommonly, some of the “symptoms” of the patient were determined to be attributed to the numerous convergent receptor properties of the 3 antipsychotics in the patient’s brain. As recently highlighted at the American Society of Clinical Psychopharmacology Annual Meeting, there are virtually no published clinical studies demonstrating improved clinical outcomes when 2 or more antipsychotics are prescribed to a treatment nonresponder.^9,10 The only exception to this is aripiprazole augmentation to clozapine after an adequate serum level has been documented for an adequate period.¹¹

Reflections

Despite expert consensus that polypharmacy with antipsychotics has no evidence of benefit and can create molecular confusion in the patient’s brain, it is quite commonly practiced. Equally perplexing to me is the lack of routine use of plasma antipsychotic levels, which provide a concrete quantification of the real-time plasma level that can highly inform the next step in the treatment plan. Plasma antipsychotic levels are hugely underutilized, despite being the standard of care as defined by experts in schizophrenia.^12,13

A significant telltale study by Potkin et al monitored 25 patients with schizophrenia or schizoaffective disorder randomly assigned to 80 mg, 120 mg, or 160 mg/day of lurasidone and used PET occupancy data paired with plasma lurasidone levels to assess correlations with D2R occupancy.¹⁴ Notably, adequate PET D2R occupancy of 65% or more was not correlated with the patients’ lurasidone dose but was correlated with plasma lurasidone levels greater than 70 ng/mL.

An extensive evidence-based published literature exists to guide us in treatment decisions with the judicious use of plasma antipsychotic levels. Meyer and Stahl’s book on this topic is an excellent resource and correlates plasma levels with D2R occupancy for many antipsychotics.¹⁵

Concluding Thoughts

For me, the past 40 years practicing psychiatry have been a great adventure. Standing on the shoulders of giants in psychopharmacological basic and clinical research has provided a sophisticated understanding of D2R antagonism and how this relates to schizophrenia. A basic understanding of the pharmacodynamics of D2R occupancy, coupled with the routine clinical use of monitoring a patient’s plasma antipsychotic level, may go a long way in improving our patients’ outcomes. With our current acumen, we may avoid many of the antipsychotic misadventures.

References

1. Siafis S, Davis JM, Leucht S. Antipsychotic drugs: from ‘major tranquilizers’ to neuroscience-based-nomenclature. Psychol Med. 2021;51(3):522-524.

2. Mosolov SN, Yaltonskaya PA. Primary and secondary negative symptoms in schizophrenia. Front Psychiatry. 2022;12:766692.

3. Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45(1):71-76.

4. Siafis S, Wu H, Wang D, et al. Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis. Mol Psychiatry. 2023;28(8):3267-3277.

5. Nord M, Farde L. Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther. 2011;17(2):97-103.

6. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605.

7. Peroutka SJ, Snyder SH. Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet. 1982;1(8273):658-659.

8. McCutcheon R, Beck K, D’Ambrosio E, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand. 2018;137(1):39-46.

9. Spangemacher M, Schmitz CN, Cumming P, et al. The sense and nonsense of antipsychotic combinations: a model for dopamine D2/3 receptor occupancy. Transl Psychiatry. 2025;15(1):348.

10. Lochmann van Bennekom MW, Gijsman HJ, Zitman FG. Antipsychotic polypharmacy in psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost effectiveness. J Psychopharmacol. 2013;27(4):327-336.

11. Siskind DJ, Lee M, Ravindran A, et al. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis. Aust N Z J Psychiatry. 2018;52(8):751-767.

12. Schoretsanitis G, Kane JM, Correll CU, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169.

13. McCutcheon RA, Pillinger T, Varvari I, et al; INTEGRATE Advisory Group. INTEGRATE: international guidelines for the algorithmic treatment of schizophrenia. Lancet Psychiatry. 2025;12(5):384-394.

14. Potkin SG, Keator DB, Kesler-West ML, et al. D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. CNS Spectr. 2014;19(2):176-181.

15. Meyer JM, Stahl SM. The Clinical Use of Antipsychotic Plasma Levels. Cambridge University Press; 2021.