Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia

Abstract

Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.

The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research

“…48 A recent study found that patients took longer to respond to treatment after a relapse of psychosis than for a first episode, even after adjustment for antipsychotic medication dose. 10 Duration of illness (>10 years vs >5 years) was a significant predictor of relapse, even with the ensured adherence of treatment with a long-acting injectable antipsychotic medication, suggesting that disease progression of schizophrenia affects response to treatment. 46 Finally, DRD2 receptor upregulation occurs on a much shorter timescale, on the order of weeks rather than years, 27 making DSP an unlikely candidate for the mechanism of treatment resistance in the study by Alphs and colleagues.…”

“…32,36 Thus, it is likely that TRS apparent at the first episode of schizophrenia is neurobiologically distinct from TRS that develops over time. 10 HYPERDOPAMINERGIC AND NORMODOPAMINERGIC SUBTYPES HYPOTHESIS Increased striatal dopamine synthesis and release capacity in vivo are linked to psychotic relapse and the development of the first psychotic episode, [51][52][53] with large effect size elevations on metaanalysis. 54 However, it has been proposed that not all patients with schizophrenia display striatal hyperdopaminergic activity and that some patients with TRS demonstrate normal dopamine regulation or even hypodopaminergic activity (Fig.…”

“…First-episode TRS may be neurobiologically distinct from TRS that develops over time 10 • DSP hypothesis only accounts for TRS in patients who initially responded to an antipsychotic 32,36 • Differences in dopamine synthesis capacity in the striatum may be present from illness onset 53,56 • Biological changes in TRS may be categorically distinct (i.e., subtypes) from or on a continuum with changes observed in treatment-responsive patients 97 Development of TRS may occur through multiple pathways • Genetic susceptibility to TRS is not exclusive to dopamine-related genes 62 • Glutamate hypothesis of TRS is supported by ○ Neuroimaging studies 24,69,70 ○ The potential involvement of glutamatergic systems in the mechanism of action of clozapine, the only drug approved to treat TRS 15,69 • Other hypotheses of TRS suggest that serotonin or inflammation and oxidative stress may be involved 82,84,88,89 Future work should address limitations to the hypotheses of the neurobiology of TRS…”

“…TRS may present from the first episode of psychosis 3,4,7 or may develop later in the disease progression. Later onset of treatment resistance may be preceded by relapses, [8][9][10] which in part may result from medication nonadherence or discontinuation. 2 However, it is critical to differentiate true TRS from pseudo-resistance (i.e., when a patient appears resistant, but treatment is inadequate rather than ineffective).…”

Frühintervention bei Schizophrenie – ein Update

“…2 Vor-und Nachteile von Depotformulierungen[42] Antipsychotikums mit einer reduzierten bzw. verzögerten Response verbunden[51].Der höchste Prädiktor für einen Rückfall ist die medikamentöse Nicht-Adhärenz, die durch verschiedene Faktoren beeinflusst wird. Wird das Antipsychotikum nach Abklingen der psychotischen Symptome abgesetzt, kommt es innerhalb eines Jahres bei durchschnittlich 77 % der Patientinnen und Patienten zum Rezidiv.…”