01. First-Episode Psychosis in Women: Which Antipsychotic Is the Preferred Choice?

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When a patient presents with a first episode of psychosis, reducing the duration of untreated psychosis through early intervention and treatment is considered the gold standard of care for optimizing clinical and functional outcomes. Yet male and female patients have long been observed to demonstrate different patterns of symptom onset and antipsychotic side effects. Should this translate to different treatment recommendations as well?

A recent study published in Schizophrenia Bulletin assembled an international panel of research and clinician experts to answer this question. Their goal was to produce clinical practice guidelines for the treatment of first-episode psychosis specifically in female patients.

No Antipsychotic Showed Clear Superiority

The authors assembled a guideline development group of experts in Women’s Health, Adult Psychiatry, Child and Adolescent Psychiatry, and Early Intervention in Psychosis. They adapted existing clinical guidelines for first-episode psychosis using an established framework for guideline production.

Through their structured exploration of existing literature and guidelines, they concluded that 80% of patients being treated for first-episode psychosis do respond to their first antipsychotic trial. They also concluded that there is no one antipsychotic with clear superiority over another in terms of clinical response.

If sex-specific differences in antipsychotic efficacy and effectiveness exist, they have not been studied well enough at this point to inform clinical guidelines.

Side Effect Priorities Drove the Recommendations

The authors therefore centered their guideline development around tolerability and individual preferences regarding side effects. Existing clinical practice guidelines already prioritize second-generation antipsychotics over first-generation antipsychotics for both sexes in order to reduce risk of extrapyramidal symptoms, and that recommendation was maintained by this study.

The group then designated hyperprolactinemia and cardiometabolic side effects — particularly weight gain — as the side effect outcomes most important to female patients. They centered their guidelines around minimizing these side effects.

Aripiprazole 5 mg as First Choice

On this basis, they ultimately recommended aripiprazole as a first-choice antipsychotic selection. They suggest starting at 5 mg daily rather than 10 mg whenever clinically reasonable to do so.

Other preferred choices for adults include:

• Brexpiprazole
• Cariprazine
• Lurasidone
• Asenapine
• Ziprasidone

For adolescents, they highlight that aripiprazole, brexpiprazole, and lurasidone are the medications on this shortlist with the most data supporting safety and efficacy in adolescents.

Notably, they strongly recommend against olanzapine, quetiapine, risperidone, and paliperidone as first-choice selections in the female patient population.

How These Recommendations Compare to General Guidelines

So do female patients require a different set of guidelines? How different are these recommendations from what would be recommended for the general patient population?

When compared to the recent international consensus guidelines around first-episode psychosis and schizophrenia treatment published in Lancet Psychiatry last year (which actually had an overlapping author list to this study) aripiprazole was recommended as an initial treatment for first-episode psychosis for both sexes. Additionally, the recommendation to start at 5 mg daily in an attempt to find the lowest effective dose was recommended for male patients as well.

So the first pick does not seem to be different, and they do not recommend different starting doses or dose uptitrations for any of the medications on their shortlist.

Peri- and Postmenopausal Patients

So does that mean I will always reach for aripiprazole for my female patients, or at least one of the medications from their shortlist? Not necessarily. I do think aripiprazole is often a reasonable recommendation, and it has the added benefit of a long-acting injectable formulation.

In this study, the main focus was on prioritizing minimal weight gain and preventing consequences of hyperprolactinemia, which may include:

• Galactorrhea
• Sexual dysfunction
• Lower fertility
• Decreased bone mineral density
• Potentially an increased risk of breast cancer

These are important side effects to minimize. Protecting bones is particularly important when treating peri- and postmenopausal patients who may already be at higher risk for fracture due to lower estrogen levels. I feel that this subset of female patients is where the study’s clinical guidelines really shine.

Pregnancy and Lactation Underemphasized

Yet considerations surrounding antipsychotic prescribing during pregnancy and lactation were only mentioned briefly in the discussion and didn’t seem to factor strongly into the main treatment recommendations. This surprised me, given that the focus was on female-specific clinical guidelines.

Half of pregnancies are unplanned, and patients with first-episode psychosis are often of reproductive age. The possibility of future pregnancy and lactation should be considered in the decision-making process from the beginning of treatment, because making medication changes and risking destabilization after conception and fetal exposure has already occurred is not considered ideal.

Aripiprazole, Prolactin, and Lactation Risk

In particular, the study generally posits it as beneficial that aripiprazole can lower prolactin levels and can be used to treat galactorrhea rather than cause it. But for many of my preconception, pregnant, and postpartum patients who plan to produce breast milk, that would be a very unwanted side effect.

Case reports have identified use of aripiprazole to be associated with difficulty establishing lactation and poor milk supply. It’s not clear at this point how early a patient would need to switch to a different medication to avoid this risk.

Others on their shortlist are newer agents with much less data on the effects on the fetus of exposure during pregnancy. While second-generation antipsychotics as a class have very reassuring findings that indicate no increased risk of congenital malformation, new medications didn’t contribute much or at all to the meta-analyses and observational studies on which this conclusion is based.

Cariprazine Lacks Pregnancy Safety Data

One of the medications on their shortlist, cariprazine, has almost no human pregnancy data available. The manufacturer specifically advises against use in pregnancy and advises highly effective contraception during treatment and for 10 weeks after discontinuing treatment.

There’s a tension here in my clinical conversations with patients, where some of the antipsychotics that do have the most available data during pregnancy and lactation are those with the most cardiometabolic side effects. In these cases, I would still keep other antipsychotics not on their list as part of the discussion.

Lurasidone and Ziprasidone Require Calories

Outside of specific reproductive considerations, it’s worth noting that two of the other antipsychotics on their shortlist — lurasidone and ziprasidone — must be eaten with a minimum number of calories for proper absorption.

Given high reported rates of restrictive eating patterns and disorders in female patients, which would presumably be enriched further amongst those most concerned about weight gain as a side effect, be sure to screen for disordered eating and confirm that they feel able to consistently take the medication as prescribed.

Bottom Line: Aripiprazole as a Reasonable First Trial

In my view, what I would see as the main takeaway of this study is that, just like in male patients, aripiprazole 5 mg is a reasonable first medication trial for first-episode psychosis in female patients.

If your patient may be planning to breastfeed in the future, discuss potential effects on lactation as part of the informed consent discussion. And when possible, trial any medication change prior to conception to ensure stability on a new regimen prior to pregnancy.

Abstract

Clinical Practice Guideline on the Choice of First Antipsychotic Medicine for Females Experiencing a First-Episode of Psychosis

Caroline Hynes-Ryan, Dolores Keating, Aoife Carolan, Bodyl Brand, Paola Dazzan, Fiona Gaughran, Margaret Hahn, Sean Halstead, Sophie Mae Harrington, Yvonne Hartnett, Ian Kelleher, John Lyne, Fiona McNicholas, Karen O’Connor, Benjamin Perry, Ewa Sadowska, Brian O’Donoghue & Iris E Sommer

Background

Early intervention in first-episode psychosis (FEP) is critical for long-term outcomes with antipsychotic medicines among the primary treatment options. However, existing clinical practice guidelines (CPGs) do not provide sex-specific recommendations, despite females experiencing distinct vulnerabilities to antipsychotic side-effects. In particular, hyperprolactinemia and cardiometabolic side-effects are associated with substantial subjective distress and potential long-term physical health risks for females across the reproductive lifespan. We aimed therefore to develop a CPG on the preferred antipsychotic medicines for females experiencing FEP.

Study Design

An international multidisciplinary panel, including experts-by-experience, used the GRADE-ADOLOPMENT process and AGREE II framework to adapt existing FEP guidelines for adults and adolescents. Key health questions were developed through stakeholder consultation and literature review. Critically important patient outcomes were prioritized, and evidence was synthesized on side-effect profiles, with recommendations agreed by consensus. The guideline algorithm was field-tested and externally reviewed by experts.

Study Results

Prolactin-elevation and cardiometabolic side-effects were prioritized in antipsychotic medicine selection for females. Medicines with higher risks—first-generation antipsychotics, olanzapine, quetiapine, risperidone, paliperidone, and amisulpride—are not recommended first-line. Aripiprazole is recommended as the preferred first-choice due to its consistently favorable prolactin and cardiometabolic profile. Alternative options with low or low-to-medium risk profiles are recommended for adults and adolescents, supported by shared decision-making tools.

Conclusions

This is the first CPG addressing antipsychotic choice for females with FEP. By prioritizing critically important patient outcomes and lived experience, the guideline supports safer, sex-sensitive prescribing for females that may improve treatment acceptability, adherence, and equity in psychosis care.

Reference

Hynes-Ryan, C., Keating, D., Carolan, A., Brand, B., Dazzan, P., Gaughran, F., Hahn, M., Halstead, S., Harrington, S., Hartnett, Y., Kelleher,I., Lyne, J., McNicholas, F., O’Connor, K., Perry, B., Sadowska, E., O’Donoghue, B. & Sommer, I. (2026). Clinical Practice Guideline on the Choice of First Antipsychotic Medicine for Females Experiencing a First-Episode of Psychosis. Schizophrenia Bulletin, Volume 52, Issue 2, March 2026, sbag023.