Low-dose and off-label use of antipsychotics: current evidence and clinical considerations
- Gesche Jürgens
- Dec 9, 2020
- 7 min read
Since the discovery of chlorpromazine in the 1950s, antipsychotics have been a cornerstone in the treatment of schizophrenia and paranoid psychosis. Beyond psychotic conditions, several antipsychotics are also approved for affective disorders (e.g., flupentixol or quetiapine for depression; aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone for treatment and prevention of mania), for delirium (haloperidol), and for persistent aggression associated with dementia or developmental disorders, where other treatments are not sufficiently effective or tolerated (risperidone, haloperidol). A few non-psychiatric indications also exist, such as movement disorders including tics and Huntington’s disease (pimozide, haloperidol), and for the prevention and treatment of postoperative nausea and vomiting (haloperidol).
Off-Label use of antipsychotic medications
Over recent years, off-label use of antipsychotic medications has expanded steadily and has become increasingly common, often at lower doses than those indicated for primary psychiatric disorders such as schizophrenia or bipolar disorder (1).
The term off-label use refers to any use of a medicine outside its approved indication(s) or conditions. This includes prescribing beyond approved indications, use in other age groups or patient populations, and administration in different doses or via routes not specified in the Summary of Product Characteristics (SmPC).
It is the responsibility of the pharmaceutical company wishing to place a product on the market to apply for approval from the health authorities, who then determine, based on a risk-benefit assessment, whether the proposed conditions can be authorized. Subsequently, it is solely the company’s decision whether to seek an extension of indication if new research demonstrates clinical efficacy in another condition (2).
Thus, the concept of off-label use encompasses both scientifically justified indications and more questionable practices that may result in ineffective or potentially harmful treatment, as adequate safety assessments have not been conducted before clinical implementation. Regarding low-dose antipsychotic use, both scenarios coexist.
Scope and trends
A recent systematic review revealed a high prevalence of off-label antipsychotic prescribing among children and adolescents, where approximately 66% of young people receiving antipsychotics are treated off-label. Off-label use is widespread for mood and behavioral disorders, but also for tic disorders, irritability associated with autism, and other neurodevelopmental conditions. The most frequently implicated agents are second-generation antipsychotics (SGAs), notably quetiapine, olanzapine, and risperidone (1).
Among adults, the same review found that 30–60% of all antipsychotic prescriptions are off-label, largely driven by SGAs such as quetiapine, often used for non-psychotic conditions including mood and anxiety disorders, sleep disturbance, and behavioral symptoms in dementia (1).
Quetiapine: dose-dependent effects and uncertainties
Quetiapine has, in recent years, gained popularity as a sedative (3). Approved for the treatment of psychosis and bipolar disorder, the usual maintenance dose ranges from 400–800 mg/day. However, quetiapine displays a dose-dependent receptor-binding profile: at 25–150 mg/day, it exhibits high affinity for H₁-histamine receptors, resulting in strong sedative effects at sub-antipsychotic doses (4). This has led to widespread low-dose, off-label prescribing with varying degrees of scientific support (5,6).
A recent meta-analysis of 21 clinical trials found that quetiapine improved sleep quality and increased total sleep time compared with placebo at doses of 50–300 mg, but not at 25 mg, and that effects were not superior to those of haloperidol or mirtazapine. Meta-regressions showed that older age (>66 years) and male sex predicted better responses, whereas dosage did not. Notably, patients with anxiety or major depressive disorder demonstrated narrower confidence intervals, suggesting more consistent effects than in healthy volunteers. Nevertheless, adverse events and treatment discontinuations due to side effects were common across all quetiapine groups (5). This observation is consistent with epidemiological evidence showing that even low-dose quetiapine is associated with metabolic adverse effects, including weight gain, dyslipidemia, and elevated HbA1c levels, indicating that such risks are not restricted to high-dose or long-term use (7).
Taken together, these findings indicate considerable uncertainty regarding the generalizability of quetiapine’s sedative effects and the optimal dosing range for this indication. Moreover, low doses do not preclude adverse effects, highlighting the need for careful monitoring of tolerability and safety.
Aripiprazole: a contrasting mechanism
In contrast to quetiapine, the low-dose use of aripiprazole represents a different therapeutic rationale. Here, the goal is not to repurpose a side effect but to counteract adverse effects induced by other antipsychotics. Low-dose aripiprazole has therefore been employed as an adjunctive treatment to alleviate antipsychotic-induced hyperprolactinemia and to reduce metabolic complications.
Aripiprazole differs fundamentally from most other antipsychotics in its receptor pharmacology and resulting tolerability profile. Whereas first-generation agents (FGAs) and many second-generation antipsychotics (SGAs) act as dopamine D₂ receptor antagonists, aripiprazole functions as a partial D₂ agonist, stabilizing rather than blocking dopaminergic transmission (8). This mechanism confers a lower risk of extrapyramidal symptoms and tardive dyskinesia, while also normalizing prolactin levels without compromising antipsychotic efficacy.
The standard maintenance dose for schizophrenia or mania is 10–30 mg/day, but several studies show that low doses (≈ 5 mg/day) can effectively reduce prolactin levels and improve symptoms of hyperprolactinemia (9,10). Because aripiprazole has minimal affinity for H₁-histamine and muscarinic receptors, it is associated with less sedation, weight gain, and anticholinergic effects (11).
By contrast, SGAs such as olanzapine, clozapine, and quetiapine exhibit high H₁ receptor affinity, leading to an increased risk of sedation, weight gain, and metabolic dysregulation. Aripiprazole’s receptor selectivity thus confers a more favorable metabolic and endocrine profile, and adjunctive or switching strategies involving aripiprazole have been explored as ways to prevent or reduce metabolic complications such as dyslipidemia and insulin resistance.
Even at low doses, antipsychotics are not benign. Adverse effects such as metabolic, cardiovascular, neurological, and sedative are generally class-related rather than strictly dose-dependent.
Several clinical studies have specifically examined whether adjunctive aripiprazole can counteract clozapine-associated metabolic disturbances. In a prospective study, Gupta et al. (2021) evaluated a fixed low dose of 5 mg/day added to ongoing clozapine therapy and found significant reductions in body weight and total cholesterol after 24 weeks, suggesting that even low-dose aripiprazole may improve metabolic parameters without compromising psychiatric stability (12). Similarly, Fleischhacker et al. (2010) reported greater metabolic improvements, including reductions in weight, BMI, triglycerides, and total cholesterol, when using flexible dosing between 5 and 15 mg/day (mean 11.1 mg). The somewhat stronger effects observed in that study likely reflect the higher average dose and longer treatment duration (13).
Taken together, these findings indicate that adjunctive aripiprazole can attenuate clozapine-related metabolic side effects, with the magnitude of benefit appearing dose-dependent. Low-dose regimens (≈ 5 mg/day) may yield modest improvements in lipid and weight measures, whereas higher doses may provide broader metabolic benefits. Nevertheless, the overall evidence remains limited, and further long-term randomized trials are warranted to determine optimal dosing and confirm clinical significance.
Safety and risk considerations
Even at low doses, antipsychotics are not benign. Adverse effects such as metabolic, cardiovascular, neurological, and sedative are generally class-related rather than strictly dose-dependent. In older adults, particularly those with dementia or delirium, low-dose use has been linked to falls, orthostatic hypotension, stroke, and increased mortality (14).
Clinical implications
From a clinical-pharmacological perspective, off-label, low-dose use of antipsychotics may be justified in selected cases, for instance, when evidence-based alternatives have failed or are contraindicated. Such prescribing should always include a clear therapeutic rationale, defined target symptoms, a time-limited trial period, and regular reassessment of efficacy and tolerability. Non-pharmacological interventions should be prioritized whenever possible. Importantly, low dose does not mean low risk; metabolic and cardiovascular side effects may occur even at minimal exposure.
Conclusion
The off-label and low-dose use of antipsychotics represents a complex and heterogeneous clinical practice. While such prescribing often attempts to address unmet clinical needs, it also exposes important gaps in the evidence base. Certain applications, such as the use of low-dose quetiapine for sleep disorders or adjunctive aripiprazole for antipsychotic-induced hyperprolactinemia, may be pharmacologically plausible and clinically beneficial in selected patients. However, these uses are supported by variable and indication-specific levels of evidence and require individualized assessment of risks and benefits.
Low-dose does not equate to low risk, and even minimal exposure may lead to metabolic, cardiovascular, or neurological side effects. Therefore, off-label prescribing should be guided by clear therapeutic rationale, explicit treatment goals, and regular reassessment of efficacy and tolerability. When applied judiciously and within a well-documented framework, off-label use can serve as a pragmatic extension of evidence-based practice rather than a departure from it. Continued research is essential to define safe and effective low-dose regimens better and identify patient populations most likely to benefit. □
This manuscript was language-edited and formatted with assistance from ChatGPT-5 (OpenAI). The intellectual content, interpretations, and conclusions are entirely the author’s own.
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