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. Author manuscript; available in PMC: 2025 Nov 25.
Published in final edited form as: Am J Psychiatry. 2025 Feb 19;182(4):341–348. doi: 10.1176/appi.ajp.20240321

Continuous Dopamine D2 Receptor Blockade and Long-Term Outcome in First-Episode Schizophrenia

Jari Tiihonen 1,2,3, Antti Tanskanen 4,5,6, Marco Solmi 7,8,9,10, Jose M Rubio 11,12,13, Christoph U Correll 14,15,16,17, John M Kane 18,19,20, Heidi Taipale 21,22,23,24
PMCID: PMC12643106  NIHMSID: NIHMS2114058  PMID: 39967411

Abstract

Objective:

It is not known what proportion of patients experience relapse in first-episode schizophrenia despite continuous dopamine D2 receptor blockade and whether breakthrough psychosis is attributable to long-term use of D2-blocking antipsychotics. Using data from a Finnish nationwide cohort, the authors sought to test the hypothesis that the incidence of breakthrough psychosis is accelerated among previously relapse-free patients receiving continuous D2 antagonist treatment beyond 5 years.

Methods:

All persons age 45 years or younger with first-episode schizophrenia were identified from the nationwide registry of inpatient care for the years 1996–2014. The primary outcome was a severe relapse leading to hospitalization among those treated continuously with long-acting injectable (LAI) antipsychotics. The secondary outcome was the incidence rate ratio (IRR) of relapse during years 2–10, using year 1 as the reference.

Results:

A total of 305 patients initiated ensured LAI use during the first 30 days of follow-up. Kaplan-Meier analysis showed that during the 10-year follow-up, their cumulative probability of relapse was 45% (95% CI=35–57). The annual relapse incidence per person-year decreased from 0.26 (95% CI=0.20–0.35) during the first year to 0.05 (95% CI=0.01–0.19) during the fifth year, corresponding to an IRR of 0.18 (95% CI=0.04–0.74). During years 6–10, only four relapses occurred during 128 person-years, corresponding to an IRR of 0.12 (95% CI=0.03–0.33) compared with year 1.

Conclusions:

About 40%–50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade, apparently due to non-dopaminergic elements of the pathophysiology of the illness, as the results show that long-term dopamine receptor blockade is not associated with an increased risk of breakthrough psychosis.

During the past 70 years, all antipsychotic medications approved for treatment of schizophrenia, with the exception of the recently introduced xanomeline-trospium (1), have been dopamine D2 receptor antagonists, and they have often been proven effective in the treatment of acute psychotic episodes and maintenance treatment up to 1 year (2–5). However, it has remained unknown what proportion of patients remain relapse-free if they receive continuous dopamine antagonist treatment starting immediately after the first schizophrenia diagnosis. D2 receptor blockade has been observed to result in a compensatory upregulation of high-affinity states in these receptors in rodents (6). Positron emission tomography data in humans have been limited to between-patient comparisons suggesting greater D2 sensitivity in chronic versus early-phase patients, with no within-subject measurements (7). Animal data have shown development of tolerance to “chronic” antipsychotic treatment (8), yet the translation of this finding to humans is equivocal. In humans, this effect might lead to dopamine supersensitivity, causing reduction of antipsychotic efficacy after long-term antipsychotic exposure (9–11). This idea is supported by a few observational studies reporting that up to 70% of patients on long-term maintenance treatment have psychotic symptoms during 7- to 20-year follow-up, and that patients with shorter treatment duration and lower antipsychotic dosages may have better outcomes (12, 13). It should be noted that these studies could not verify the actual amount of medication used, and it is unknown how much patient selection, confounding by indication (i.e., patients with less severe symptoms and non-schizophrenia psychoses being offered lower antipsychotic dosages or shorter duration of antipsychotic treatment), and attrition bias contributed to the results (14, 15). Also, a recent randomized controlled trial showed that antipsychotic dosage reduction was not beneficial to functional outcome (16).

A meta-analysis of relapse prevention trials with ensured use of long-acting injectable (LAI) antipsychotics found a relapse rate of 28% during a mean follow-up period of 71.5 weeks (17), and a large nationwide observational study found that the incidence of breakthrough psychosis was 31.5% during a mean duration of 441 days of LAI treatment (18). Since a large proportion of patients in clinical studies have had multi-episode schizophrenia, it remains unknown what the results might be among first-episode patients, for whom the lifetime cumulative antipsychotic exposure can be reliably quantified, and whether breakthrough psychosis in first-episode schizophrenia is related to long-term D2 blockade rather than neurobiological damage occurring due to successive relapses in chronic patients. To our knowledge, only one study has investigated the incidence of breakthrough psychosis during ensured antipsychotic treatment among patients with first-episode schizophrenia on maintenance treatment, and it found that about one in five patients developed breakthrough psychosis during 2-year follow-up (19; see also 20). Therefore, it has been questioned whether the results from randomized controlled trials that last only up to 24 months can be applied to long-term outcomes, and it has been noted that the “50-year-old debate between targeted and continuous treatment schemes” is still topical (21).

Here, we present data from a national cohort of first-episode schizophrenia patients for whom lifetime cumulative antipsychotic exposure could be reliably quantified by their treatment with LAIs, for which the confounder of nonadherence is removed. We sought to test the hypothesis that the incidence of breakthrough psychosis is accelerated among previously relapse-free patients receiving continuous D2 antagonist treatment beyond 5 years.

METHODS

The study data were drawn from the official national registers, and all individuals were pseudonymized with coding numbers. Persons with incident schizophrenia were identified from the base cohort that includes all persons hospitalized due to schizophrenia during the period 1972–2014 in Finland. Their records were retrieved from the nationwide Hospital Discharge Register, which contains records on all inpatient hospital stays. Schizophrenia was defined as ICD-8 and ICD-9 code 295 and ICD-10 codes F20 and F25. Persons with first-time hospitalization for schizophrenia were identified during the period 1996–2014 (N=23,499). To ensure first-episode status, given that some individuals may have been treated in primary care prior to their first hospitalization, we excluded persons who had used antipsychotic drugs during the year preceding the hospitalization and persons who were over age 45 at first diagnosis. This approach resulted in a cohort of 5,367 incident cases. Sex is coded in the registers at birth or immigration, but it can be changed later if the person applies for an official change in their sex designation. Race and ethnicity are not registered in health care records in Finland. Permissions for this study were granted by the pertinent institutional authorities at the National Institute for Health and Welfare of Finland, the Social Insurance Institution of Finland, and Statistics Finland.

Antipsychotic use was derived from the Prescription Register data as Anatomical Therapeutic Chemical [ATC] classification code N05A (excluding lithium, N05AN01). The register includes information on all reimbursed medication dispensation from Finnish pharmacies to all residents since 1995, and it contains the ATC code, the date of dispensing, the number of packages dispensed, and the dispensed amount in defined daily doses (DDDs) as defined by the World Health Organization (22). For example, the standard dosage (1 DDD per day) is 5 mg for oral risperidone, 10 mg for oral olanzapine, and 15 mg for oral aripiprazole. The PRE2DUP method (23) was used for constructing antipsychotic use periods, that is, when continuous use started and ended. This method is based on mathematical modeling of personal drug purchasing behavior from the dispensing data. The method estimates drug use periods based on individual purchase histories (dates, dispensed amounts) and according to drug package–specific parameters, by taking into account variation in purchase events caused by irregularities such as stockpiling of drugs and periods in hospital care when drugs are provided by the caring unit and not recorded in the register data. Each ATC code and drug form of each ATC code (i.e., oral vs. LAI) was modeled separately. In the postprocessing phase, use periods were further grouped as “any LAI,” referring to continuous use of LAIs. All patients using LAIs were classified as LAI patients, regardless of whether or not they used additional oral antipsychotics, and calculations of the DDDs used included all antipsychotics for the LAI group, including add-on oral antipsychotics. Patients who did not initiate LAIs during the first 30 days were categorized as “other,” that is, patients with no antipsychotic use, intermittent antipsychotic use, or antipsychotic use that was not ensured. Not ensured antipsychotic use also included patients with continuous purchases of oral antipsychotics. Antipsychotic nonuse periods were constructed between use periods and by separating periods in hospital care from both use and nonuse periods.

The primary outcome was the proportion of patients with a severe relapse leading to hospitalization among those treated continuously with LAIs. The secondary outcome was the incidence rate ratio during years 2–10, using year 1 as the reference. Relapse was defined as a hospital care period with any of ICD-10 codes F20–F29 recorded as the main discharge diagnosis. For analyses of continuous medication use, a period of 30 days after the first discharge was used as a time window to define exposure status for each person. Exposure categories were LAI and other (i.e., use of intermittent/not ensured oral antipsychotics or nonuse of antipsychotics). The period of 30 days was chosen to ensure that persons who were initiated on LAIs during hospital care had a reasonable time to receive the LAI in outpatient care. Persons who relapsed during the 30-day exposure definition period were excluded, as their exposure status could not be determined (N=579). The follow-up period started 30 days after the first discharge in the defined exposure category and ended with the first occurrence of any of the following: change in exposure category (switch of medications [not between LAIs], discontinuation of use among antipsychotic use category patients, or initiation of use among nonuse category patients); relapse; other hospital care of ≥5 days for reasons other than relapse; death; end of data linkage (December 31, 2017); or 10 years after cohort entry. The minimum follow-up time frame was 3 years for all patients (between December 31, 2014, and December 31, 2017).

The cumulative probability of relapse was computed using the Kaplan-Meier method, by taking into account death, discontinuation or switch of medication, and somatic hospitalization as competing reasons for the end of follow-up. The cumulative relapse rate was compared between LAI users and others by log-rank test.

The incidence of relapse was calculated by dividing the number of events by person-years during each time period of interest. Incidence rate ratios for years 2, 3, 4, 5, and 6–10 were calculated by using year 1 as the reference. Estimates of relapse incidence or incidence rate ratios were calculated using two Poisson type models: a one-factor generalized linear model with Poisson distribution and a log link function, or a longitudinal random-effects Poisson regression model (unstructured correlation structure), as appropriate. The Poisson regression models were tested using the goodness-of-fit test, and the assumptions of overdispersion in models were tested using the Lagrange multiplier test. Poisson model goodness-of-fit showed a good fit in models (all tested p values were >0.12), and Lagrange multiplier tests showed no overdispersion (all tested p values were >0.22). Follow-up time (exposure time) in Poisson models was set with the coefficient “ln(person-years),” limited to one time. The prevalence of anticholinergic antiparkinsonian drugs, defined as ATC code N04AA, was compared between groups. Stata, version 18.0, was used for the analysis, and SAS, version 9.4, for data management.

RESULTS

After exclusion of 14,780 patients who used antipsychotics during the year preceding their hospitalization, a total of 4,788 patients were included in the study. Of these, 3,078 (64.3%) were men, and 1,710 (35.7%) were women. Their mean age at the start of follow-up was 29.5 years (SD=7.8, median=28, interquartile range [IQR]=23–35). A total of 305 patients initiated LAIs within the first 30 days. Of these, 202 (66.2%) were men, the mean age was 31.7 years (SD=7.5), and the median duration of the first hospitalization was 83 days (IQR=53–141). The corresponding figures for the other patients (N=4,483) were 64.2% men (N=2,876), a mean age of 29.4 years (SD=7.8), and a median duration of 72 days (IQR=36–153) for the first hospitalization. Among the 305 patients who were treated with LAIs, 122 (40%) received risperidone, 57 (19%) received zuclopenthixol, 52 (17%) received perphenazine, 32 (10%) received olanzapine, 23 (8%) received haloperidol, and 19 (6%) received other LAIs.

Table 1 shows the numbers and proportions of competing causes of censoring during follow-up. Figure 1A shows the cumulative probability of relapse during the first year of treatment. The curves for LAIs and other antipsychotic treatments were aligned through the first 5 months, after which they diverged. The highest incidence of relapse among LAI-treated patients occurred during the first 2 months, after which the incidence started to decline. As shown in Table 2, the incidence of relapse per person-year among patients with LAIs was 0.51 (95% CI=0.34–0.76) for months 2–3, and it declined to 0.11 (95% CI=0.04–0.28) for months 9–12.

TABLE 1.

Reasons for end of follow-up among patients not rehospitalized during the first 30 days who were on continuous long-acting injectable (LAI) antipsychotic treatment and those who were nota

N at Start of Follow-Up
 Switch or Discontinuation
 Other Hospitalization
 Relapse
 Death
 End of Follow-Up
Group N N % N % N % N % N %
LAI users 305
 Through 5 years 130 42.6 55 18.0 66 21.6 6 2.0 48 15.7
 Through 10 years 131 43.0 56 18.4 70 23.0 8 2.6 40 13.1
Other patients 4,483
 Through 5 years 86 1.9 915 20.4 1,817 40.5 85 1.9 1,580 35.2
 Through 10 years 109 2.4 1,037 23.1 1,994 44.5 110 2.5 1,233 27.5
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a

Other patients are those not on LAI treatment, with no/intermittent/not ensured antipsychotic use. “End of follow-up” indicates censoring at 10 years of follow-up or at end of data linkage. In the group “other,” switch indicates switch to LAI, but not from one oral antipsychotic to another. A total of 2,570 (57.3%) of the patients in this group had periods of nonuse of antipsychotics before censoring. “Other hospitalization” refers to any hospital stay of ≥5 days other than for relapse.

FIGURE 1. Kaplan-Meier analysis of cumulative probability of relapse among patients on continuous long-acting injectable (LAI) antipsychotic treatment (N=305) and all other patients during the first year and across 10 years (N=4,483)a.

FIGURE 1.

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a Other patients are those not on LAI treatment, with no/intermittent/not ensured antipsychotic use. Shaded areas indicate 95% confidence intervals. The monthly and annual numbers of relapses and person-years for patients on LAIs are shown in Table 2.

TABLE 2.

Number of relapses and person-years during the first year and during the 10-year follow-up among patients on continuous long-acting injectable antipsychotic treatment

Time Frame Relapses Person-Years Incidence Rate 95% CI
Months
2–3 23 45.5 0.51 0.34, 0.76
3–6 17 53.8 0.32 0.20, 0.51
6–9 3 43.2 0.07 0.02, 0.22
9–12 4 37.5 0.11 0.04, 0.28
Years
1–5 66 481.9 0.14 0.11, 0.17
6–10 4 128.4 0.03 0.01, 0.08
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Figure 1B shows the cumulative probability of relapse during the first 10 years of treatment, which was 45.2% (95% CI=34.8–57.2) among patients with continuous LAI treatment and 55.2% (95% CI=53.5–57.0) among patients with no/intermittent/not ensured use of antipsychotics. Figure 2 shows the relapse incidence per person-year during the periods of 1–5 years and 6–10 years among patients continuously using LAIs. Among patients on continuous LAI treatment, the relapse incidence per person-year decreased from 0.26 (95% CI=0.20–0.35) during year 1 to 0.05 (95% CI=0.01–0.19) during year 5. The corresponding incidence rate ratio (IRR) compared with year 1 was 0.18 (95% CI=0.04–0.74) for year 5 (p=0.005 for the difference between year 5 and year 1). For years 2–5, the IRR was 0.24 (95% CI=0.14–0.41). During years 6–10, only four relapses occurred during 128 person-years, corresponding to an incidence of 0.03 (95% CI=0.01–0.08) and an IRR of 0.12 (95% CI=0.03–0.33, p<0.0001) compared with year 1. The numbers of relapses and person-years, incidence rates, and incidence rate ratios are shown in Tables 2 and 3. The cumulative incidence of relapse was substantially lower among patients using LAIs compared with the other patients (p=0.002).

FIGURE 2. Relapse incidence rate per person-year during years 1–5 and years 6–10 (left), and the incidence rate ratio during years 2–5 and years 6–10 (right) among patients on continuous long-acting injectable antipsychotic treatmenta.

FIGURE 2.

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a Error bars indicate 95% confidence intervals. The incidences and incidence rate ratios are shown in Tables 2 and 3.

TABLE 3.

Annual incidence rate ratios (IRRs) per person-year during the 10-year follow-up among patients on continuous long-acting injectable antipsychotic treatment

Year IRR 95% CI
1 1 1, 1
2 0.27 0.13, 0.56
3 0.27 0.12, 0.63
4 0.19 0.06, 0.63
5 0.18 0.04, 0.74
6 0.12 0.02, 0.85
7 0.13 0.02, 0.95
8 0.15 0.02, 1.10
9 0.00 0.00, 0.00
10 0.20 0.03, 1.43
2–5 0.24 0.14, 0.41
6–10 0.12 0.03, 0.33
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Table 4 shows the median antipsychotic dosages during follow-up among patients with LAIs, showing a decrease in the dosage as a function of time. The use of anticholinergic antiparkinsonian drugs was identical among LAI patients who had relapses (13/70, 18.6%) and those who did not (45/235, 19.1%).

TABLE 4.

Antipsychotic dosage (as defined daily doses per day) by year for patients on continuous long-acting injectable antipsychotic (LAI) treatment and other patients during the 10-year follow-upa

LAI Users
 Other Patients
Year N Median IQR N Median IQR
1 305 1.20 0.93–1.62 3,436 1.03 0.66–1.63
2 138 1.07 0.72–1.45 2,075 0.98 0.58–1.52
3 97 1.03 0.73–1.37 1,626 0.99 0.57–1.56
4 72 1.01 0.72–1.44 1,343 0.99 0.55–1.58
5 47 0.99 0.67–1.39 1,131 0.98 0.54–1.55
6 36 1.02 0.66–1.36 972 0.99 0.58–1.62
7 31 0.99 0.67–1.51 843 0.96 0.58–1.60
8 26 1.09 0.85–1.32 745 0.98 0.55–1.54
9 23 1.03 0.74–2.32 656 0.98 0.57–1.52
10 21 1.04 0.74–1.97 580 0.97 0.56–1.49
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a

The medians and interquartile ranges (IQR) of annual antipsychotic doses are expressed as defined daily doses (22) during the 10-year follow-up.

DISCUSSION

Our results show that in Kaplan-Meier analyses taking into account patient-years at risk, the cumulative probability of relapse was 45% among patients using LAIs during 10 years of follow-up. A previous study found that up to 70% in a cohort of 70 patients with schizophrenia spectrum disorders who received antipsychotic treatment had at least mild psychotic symptoms during a 20-year follow-up (13). Antidopaminergic antipsychotic treatments are efficacious among patients with first-episode schizophrenia, but their effectiveness decreases after successive relapses (24). Since no long-term studies with ensured continuous treatment have been conducted previously, it has remained unknown how large a proportion of patients could remain relapse-free if they received continuous D2 antagonist treatment starting from the first episode. The strength of our work lies in providing, for the first time, long-term data for an entire national cohort of individuals with first-episode schizophrenia for whom antipsychotic exposure is not confounded by treatment nonadherence. In Finland, patients on LAI treatment receive their injections from public sector nurses, who document each injection in patient records. They also closely monitor treatment adherence and contact patients in cases of missed appointments. Dispensing data reflect the medication administration practice closely, although actual administration dates were not available for the study. Therefore, treatment adherence can be estimated with rather high confidence. The group “other” was included to contextualize the results with the outcome among patients receiving standard care, since initiation of an LAI immediately after the first episode is rare. The difference in the absolute risk of relapse between the two groups was 10 percentage points, corresponding to a number needed to treat of 10.

Our results show that continuous cumulative D2 blockade up to a period of 10 years is associated with a progressive decrease, rather than an increase, in the risk of breakthrough psychosis, which has been a focus of research before (18–20, 25), but without focusing on long-term (beyond 2 years) outcome among first-episode patients. Since relapse is associated with a decrease in the subsequent efficacy of antipsychotics (24), the results obtained from chronic patients with several relapses cannot reveal the full potential of antipsychotic treatments. To our knowledge, this is the first long-term study investigating the risk of relapse as a function of duration of ensured dopamine D2 receptor blockade in first-episode schizophrenia. Our results argue against breakthrough psychosis being attributable to long-term D2 blockade and putative development of dopamine supersensitivity, as suggested previously (9–11), but rather being attributable to a heterogeneous neurobiological pathophysiology of schizophrenia, indicating that neurotransmitters other than dopamine or other biological processes likely contribute to reemerging symptoms (26). Indeed, medications with different pharmacodynamic profiles have demonstrated rather similar efficacy in schizophrenia (3), yet with heterogeneous tolerability (27), and emerging treatment options with novel mechanisms of action have confirmed that symptoms of schizophrenia are sustained by complex mechanisms that go well beyond dopamine (28).

Dopamine supersensitivity as a theory is based on the observation most clearly made for the GABAergic system, for which chronic pharmacological stimulation results in downregulation of the sensitivity of the system to maintain homeostasis (29). Whether the reverse occurs for the dopaminergic system as a consequence of chronic receptor blockade by antipsychotic drugs is controversial, as this theory is based only on conflicting, indirect evidence (14, 15, 29, 30). The neurobiological data examining this phenomenon are limited, but a recent study (31) examining the changes in the dopamine system that predicted relapse upon treatment discontinuation in early-phase schizophrenia patients for whom maintenance antipsychotic treatment was discontinued failed to find an increment in dopamine sensitivity associated with greater risk of relapse. Instead, it reported that changes in dopamine synthesis capacity after treatment discontinuation predicted relapse. Alternatively, a pilot study revealed that functional connectivity in the striatum, the region where most D2 receptors in the brain are concentrated, was most aberrant for individuals with breakthrough psychosis compared to relapse in nonadherent individuals, suggesting a striatal mechanism for breakthrough psychosis (32), which could be related to changes in the dopaminergic system.

Our recent study in this same nationwide cohort of first-episode patients with schizophrenia (24) observed that standard dosages were superior to low dosages in relapse prevention. The number of relapses was a pivotal factor for antipsychotic dosage escalation: among patients with relapses, the mean antipsychotic dosage increased gradually after each new relapse from 1.22 DDDs per day before the first relapse to 1.56 DDDs per day after the fourth relapse. Among patients without relapses, the antipsychotic dosage decreased from 1.24 DDDs per day to 1.1 DDDs per day during the 5-year follow-up, indicating that long-term antipsychotic use per se does not lead to dosage escalation, but to dosage decrease, and that in addition to the initial severity of the illness, the neurobiological damage related to relapses—mainly induced by nonuse of antipsychotics—may be the cause of the increased risk for relapses (and dosage increases in patients with relapses [24]). This is also supported by the observation that the relapse risk remains high for several years after antipsychotic discontinuation, indicating that relapse is not caused by a rebound effect (33). Dopamine receptor blockade by antipsychotics is considered to lead to compensatory upregulation of D2 receptors, which leads to a need for an increase dosage, which leads to D2 upregulation, and so on. Our results showed that the median antipsychotic dosages decreased from 1.20 DDDs to 1.04 DDDs during the 10-year follow-up, which also does not support development of supersensitivity. Also, use of anticholinergic antiparkinsonian medication for extrapyramidal symptoms was nearly identical between LAI patients who relapsed and those who did not, suggesting that breakthrough psychosis among these patients was not associated with antidopaminergic side effects. It should be noted that while the cumulative probability of relapse was 45% during ensured D2 blockade, we do not know how large a proportion of the 55% without relapse did not relapse owing to their LAI use.

The strength of this study is that all data were gathered prospectively from national databases that include all individuals in Finland. The large, comprehensive unselected patient cohort and high statistical power allowed us to determine reliably the outcomes related to antipsychotic exposure and nonexposure. With the validated drug use modeling method PRE2DUP (23), we were able to ensure that LAI users actually had continuous antipsychotic exposure, and thus continuous D2 blockade, throughout a follow-up period of up to 10 years.

Several limitations should be considered when interpreting the results. First, our results apply only to the patients who were hospitalized at least once, and the relapses include only severe ones that led to hospitalization. Second, the results may have been exposed to “event bias” if those most likely to stay on LAI treatment long-term were those with the best prognosis. At the moment, there is no consensus on whether antipsychotic treatment should be continued or discontinued in the subgroup of patients with first-episode schizophrenia who have remained relapse-free for the first 2–5 years (34). Since several high-profile publications (9–13, 21) have suggested that antipsychotic treatments lose their efficacy during long-term use, our focus was on the 5- to 10-year outcome to verify or falsify this hypothesis in the subgroup of patients who were relapse-free through 5 years of illness. Our results show that the relapse incidence rate ratio was highest during the first year, decreased during years 2–5, and then plateaued after 5 years, as seen in Table 3. We can conclude that the incidence of relapse was almost negligible (about 3% per year) after the first 5 years, which indicates that the role of speculative dopamine supersensitivity is very small, if any, in the risk of breakthrough psychosis among patients who have remained relapse-free through 5 years. Schizophrenia relapse is multifactorial, since environmental factors play a role. However, we believe that stress or trauma may also converge with hyperdopaminergia-related relapse. Initiation of LAIs immediately after the first episode is infrequent, and only 40 of the 305 patients who initiated LAI treatment completed the follow-up without relapse; 70 patients experience relapse, and large proportions of patients discontinued or switched their treatment to oral (not ensured) antipsychotic treatment. High attrition is unavoidable during a long follow-up, but in this study the essential issue was to observe what happens to those patients who are exposed to ensured D2 receptor blockade beyond 2 years, which has not previously been possible. A large proportion of the patients who discontinued LAIs may have relapsed, but that information was beyond the scope of this study. Our study included only hospitalized patients, and rehospitalization was a marker of a relapse. Therefore, our results apply to patients with relatively severe symptoms.

In summary, we found that the risk of relapse during continuous and ensured antipsychotic exposure in a national first-episode psychosis cohort decreased over time, providing results that do not support the main tenet of the dopamine supersensitivity psychosis theory. The results also show that among about 40%–50% of patients with schizophrenia, relapses cannot be prevented by continuous D2 receptor blockade, indicating a need for treatments with novel mechanisms of action.

Acknowledgments

Supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Dr. Taipale was supported by a grant from the Sigrid Jusélius Foundation.

Drs. Tiihonen, Tanskanen, and Taipale have participated in research projects funded by grants to their employing institution from Janssen-Cilag and Eli Lilly. Dr. Tiihonen has served as a consultant for or received honoraria or lecture fees from HLS Therapeutics, Janssen, Lundbeck, Orion, Otsuka, and WebMed Global. Dr. Solmi has served as a consultant for AbbVie, Angelini, Boehringer Ingelheim, Lundbeck, and Otsuka. Dr. Rubio has served as a consultant or adviser for or received honoraria from Janssen, Karuna, and TEVA, and he has received grant support from Alkermes and Neurocrine and royalties from UpToDate. Dr. Correll has served as a consultant and/or adviser to or received honoraria from AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, Medincell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris; he has provided expert testimony for Janssen and Otsuka; he has served on data safety monitoring boards for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; he has received grant support from Janssen and Takeda; he receives royalties from UpToDate; and he holds stock options in Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. Dr. Kane has served as a consultant and/or adviser for or received honoraria from Alkermes, Biogen, Boehringer-Ingelheim, Bristol Meyers Squibb, Cerevel, Click Therapies, Dainippon Sumitomo, HLS, Intra-Cellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, Merck, Neurocrine, Newron, Otsuka, Saladax, Sumitomo Pharma America, Sunovion, Takeda, and Teva; he has received grant support from Janssen, Lundbeck, Merck, and Otsuka; and he is a shareholder in Cerevel, Karuna, LB Pharma, Health Rhythms, North Shore Therapeutics, and Vanguard Research Group. Dr. Taipale has received personal fees from Gedeon Richter, Janssen, Lundbeck, and Otsuka.

Continuing Medical Education

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Examination Questions for “Continuous Dopamine D2 Receptor Blockade and Long-Term Outcome in First-Episode Schizophrenia”

1. What proportion of patients with first-episode schizophrenia relapse despite continuous dopamine 2 receptor blockade during the first 10 years of treatment?

  1. About 10–20%

  2. About 20–30%

  3. About 40–50%

  4. About 70–80%

2. The cumulative incidence of severe relapse leading to hospitalization was

  1. Substantially higher among patients with LAI compared with the other patients

  2. Slightly higher among patients with LAI compared with the other patients

  3. The same among patients with LAI compared with the other patients

  4. Substantially lower among patients with LAI compared with the other patients

3. The annual incidence of breakthrough psychosis among patients using continuously LAI

  1. Decreased from the first year till the 5th year, but then increased from year 5 to year 10

  2. Decreased from the first year till the 5th year, and decreased further from year 5 to year 10

  3. Stayed constant from year 1 to year 10

  4. Increased from year 1 to year 5, and further from year 5 to year 10

Contributor Information

Jari Tiihonen, Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; Center for Psychiatry Research, Stockholm City Council, Stockholm.

Antti Tanskanen, Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; Center for Psychiatry Research, Stockholm City Council, Stockholm.

Marco Solmi, SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa; Department of Child and Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Berlin.

Jose M. Rubio, Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY.

Christoph U. Correll, Department of Child and Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Berlin Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; German Center for Mental Health, partner site Berlin.

John M. Kane, Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY.

Heidi Taipale, Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; Center for Psychiatry Research, Stockholm City Council, Stockholm; School of Pharmacy, University of Eastern Finland, Kuopio.

Data sharing statement:

Data collected for this study are proprietary to the Finnish government agencies Social Insurance Institution of Finland and National Institute for Health and Welfare, which granted the researchers permission and access to data. The data that support findings of this study are available from these authorities, but restrictions apply to the availability of these data. The code used to analyze these data is available upon request from the corresponding author for the purposes of reproducing the results.

REFERENCES

  • 1.Kaul I, Sawchak S, Correll CU, et al. : Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet 2024; 403:160–170 [DOI] [PubMed] [Google Scholar]
  • 2.Leucht S, Siafis S, Engel RR, et al. : How efficacious are antipsychotic drugs for schizophrenia? An interpretation based on 13 effect size indices. Schizophr Bull 2022; 48:27–36 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Ostuzzi G, Bertolini F, Tedeschi F, et al. : Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants. World Psychiatry 2022; 21:295–307 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Schneider-Thoma J, Chalkou K, Dörries C, et al. : Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis. Lancet 2022; 399:824–836 [DOI] [PubMed] [Google Scholar]
  • 5.Leucht S, Schneider-Thoma J, Burschinski A, et al. : Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis. World Psychiatry 2023; 22:315–324 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Seeman P, Weinshenker D, Quirion R, et al. : Dopamine supersensitivity correlates with D2(High) states, implying many paths to psychosis. Proc Natl Acad Sci U S A 2005; 102:3513–3518 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Silvestri S, Seeman MV, Negrete JC, et al. : Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl) 2000; 152:174–180 [DOI] [PubMed] [Google Scholar]
  • 8.Samaha AN, Seeman P, Stewart J, et al. : “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 2007; 27:2979–2986 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Murray RM, Quattrone D, Natesan S, et al. : Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? Br J Psychiatry 2016; 209:361–365 [DOI] [PubMed] [Google Scholar]
  • 10.Chouinard G, Samaha AN, Chouinard VA, et al. : Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Psychosom 2017; 86:189–219 [DOI] [PubMed] [Google Scholar]
  • 11.Yin J, Barr AM, Ramos-Miguel A, et al. : Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Curr Neuropharmacol 2017; 15:174–183 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Wunderink L, Nieboer RM, Wiersma D, et al. : Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70:913–920 [DOI] [PubMed] [Google Scholar]
  • 13.Harrow M, Jobe TH, Faull RN: Does treatment of schizophrenia with antipsychotic medications eliminate or reduce psychosis? A 20-year multi-follow-up study. Psychol Med 2014; 44:3007–3016 [DOI] [PubMed] [Google Scholar]
  • 14.Correll CU, Rubio JM, Kane JM: What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 2018; 17:149–160 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Fountoulakis KN, Moeller HJ, Kasper S, et al. : The report of the joint WPA/CINP workgroup on the use and usefulness of antipsychotic medication in the treatment of schizophrenia. CNS Spectr 2021; 26: 562–586 [DOI] [PubMed] [Google Scholar]
  • 16.Moncrieff J, Crellin N, Stansfeld J, et al. : Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial. Lancet Psychiatry 2023; 10:848–859 [DOI] [PubMed] [Google Scholar]
  • 17.Kishimoto T, Robenzadeh A, Leucht C, et al. : Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull 2014; 40:192–213 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Rubio JM, Taipale H, Correll CU, et al. : Psychosis breakthrough on antipsychotic maintenance: results from a nationwide study. Psychol Med 2020; 50:1356–1367 [DOI] [PubMed] [Google Scholar]
  • 19.Emsley R, Asmal L, Rubio JM, et al. : Predictors of psychosis breakthrough during 24 months of long-acting antipsychotic maintenance treatment in first episode schizophrenia. Schizophr Res 2020; 225:55–62 [DOI] [PubMed] [Google Scholar]
  • 20.Rubio JM, Schoretsanitis G, John M, et al. : Psychosis relapse during treatment with long-acting injectable antipsychotics in individuals with schizophrenia-spectrum disorders: an individual participant data meta-analysis. Lancet Psychiatry 2020; 7:749–761 [DOI] [PubMed] [Google Scholar]
  • 21.Davidson M, Carpenter WT Jr.: Targeted treatment of schizophrenia symptoms as they manifest, or continuous treatment to reduce the risk of psychosis recurrence. Schizophr Bull 2024; 50:14–21 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.World Health Organization (WHO): DDD: definition and general considerations. Oslo, Norwegian Institute of Public Health, WHO Collaborating Center for Drug Statistics Methodology, February 7, 2018. https://www.whocc.no/ddd/definition_and_general_considera/ [Google Scholar]
  • 23.Tanskanen A, Taipale H, Koponen M, et al. : From prescription drug purchases to drug use periods: a second generation method (PRE2DUP). BMC Med Inform Decis Mak 2015; 15:21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Taipale H, Tanskanen A, Correll CU, et al. : Real-world effectiveness of antipsychotic doses for relapse prevention in patients with first-episode schizophrenia in Finland: a nationwide, register-based cohort study. Lancet Psychiatry 2022; 9:271–279 [DOI] [PubMed] [Google Scholar]
  • 25.Correll CU, Sliwa JK, Najarian DM, et al. : Practical considerations for managing breakthrough psychosis and symptomatic worsening in patients with schizophrenia on long-acting injectable antipsychotics. CNS Spectr 2019; 24:354–370 [DOI] [PubMed] [Google Scholar]
  • 26.Kahn RS, Sommer IE, Murray RM, et al. : Schizophrenia. Nat Rev Dis Primers 2015; 1:15067. [DOI] [PubMed] [Google Scholar]
  • 27.Solmi M, Murru A, Pacchiarotti I, et al. : Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag 2017; 13:757–777 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Correll CU, Solmi M, Cortese S, et al. : The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents. World Psychiatry 2023; 22:48–74 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Chouinard G, Jones BD: Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 1980; 137:16–21 [DOI] [PubMed] [Google Scholar]
  • 30.Leucht S, Tardy M, Komossa K, et al. : Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071 [DOI] [PubMed] [Google Scholar]
  • 31.Kim S, Shin SH, Santangelo B, et al. : Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F] DOPA and [11C]raclopride PET study in first-episode psychosis. Mol Psychiatry 2021; 26:3476–3488 [DOI] [PubMed] [Google Scholar]
  • 32.Rubio JM, Lencz T, Barber A, et al. : Striatal functional connectivity in psychosis relapse: a hypothesis generating study. Schizophr Res 2022; 243:342–348 [DOI] [PubMed] [Google Scholar]
  • 33.Tiihonen J, Tanskanen A, Taipale H: 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry 2018; 175:765–773 [DOI] [PubMed] [Google Scholar]
  • 34.Takeuchi H, Suzuki T, Uchida H, et al. : Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms. Schizophr Res 2012; 134:219–225 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data collected for this study are proprietary to the Finnish government agencies Social Insurance Institution of Finland and National Institute for Health and Welfare, which granted the researchers permission and access to data. The data that support findings of this study are available from these authorities, but restrictions apply to the availability of these data. The code used to analyze these data is available upon request from the corresponding author for the purposes of reproducing the results.

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