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Expert Insights in Schizophrenia
Expert Insights on Schizophrenia Treatment: Your Questions Answered

Released: December 18, 2025

Joseph F. Goldberg
Joseph F. Goldberg, MD
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Key Takeaways
  • Haloperidol remains a valuable option in select clinical scenarios, particularly for acute agitation, delirium, or when metabolic adverse effects from atypical antipsychotics are a concern, although its risk for extrapyramidal symptoms limits broader use.
  • Xanomeline/trospium offers a novel, nondopaminergic approach to schizophrenia treatment, with practical considerations around titration, tolerability, and patient selection guiding its optimal use in real-world settings.
  • Personalized pharmacologic strategies, including adjunctive treatments for negative symptoms, metabolic management with GLP-1 agonists or metformin, and careful antipsychotic combinations, are essential for addressing residual symptoms and improving long-term outcomes.

Is there any place for haloperidol in 2025? If so, when would you reach for it?
Haloperidol has a time-honored tradition of use for delirium, which is thought to be a hyperdopaminergic/low cholinergic state (which haloperidol addresses well). Peak onset of action is also faster with haloperidol than with most atypical antipsychotics, which can be relevant for managing acute agitation associated with psychosis (or delirium). Haloperidol has a relatively low risk for causing metabolic dysregulation and is a viable option to treat psychosis or mania in patients for whom atypical antipsychotics with higher metabolic effects may not be options. Head-to-head studies of haloperidol versus olanzapine in acute mania or first episode psychosis find no differences in efficacy but differences in tolerability (mostly extrapyramidal symptoms [EPS] for haloperidol, sedation, and weight gain for olanzapine). Haloperidol may also be more likely than olanzapine to cause depression in bipolar disorder. Idiosyncratically, there are some patients for whom haloperidol may seem to be especially beneficial, so on a case-by-case basis, there may be unique instances in which it has value, but the risk for EPS, long-term risk for tardive dyskinesia (TD), and lack of value for depressive symptoms make it generally a less attractive option than an atypical antipsychotic.

When comparing naltrexone vs samidorphan with olanzapine, what are the clinical trade-offs, dosing, and special considerations in patients with co-occurring opioid use disorder (OUD)?
There are some very preliminary proof-of-concept data using naltrexone with olanzapine to counter weight gain. Tek and colleagues showed a 3.4-kg decrease in weight when pairing olanzapine with 25-mg/day naltrexone, as compared with a 1.37-kg increase when pairing olanzapine with placebo. That finding has not been replicated. Samidorphan has approximately 5.5 times the binding affinity at the mu opioid receptor compared with naltrexone and is supported by a more extensive and robust database for both safety and efficacy, with open-label data extending out to 4 years. Of note, both are contraindicated in patients using opioids or in acute opioid withdrawal; patients should be opioid free to avoid precipitated withdrawal.

What are your thoughts on using xanomeline/trospium (X/T) as an add-on to current pharmacotherapy, or adding something onto X/T if it is started first?
It is not unreasonable to add X/T to any nonanticholinergic antipsychotic (ie, not olanzapine, quetiapine, clozapine, or low-potency first-generation antipsychotics) or vice versa, although the manufacturer conducted their studies as monotherapy and therefore is not permitted by the FDA to promote their product specifically for purposes of adjunctive treatment. They conducted an adjunctive therapy trial (adding X/T vs placebo to aripiprazole or risperidone) called ARISE, which has not yet been published. The findings failed to show an overall benefit for X/T over placebo, but post hoc analyses suggested potential value as an augmentation to aripiprazole but not risperidone.

What would be your approach to persistent negative symptoms? What are your considerations for combining medications for residual symptoms and/or adverse effects?
Negative symptoms are very difficult to treat, and there is no singular best medication strategy. Dopamine partial agonists (eg, aripiprazole, brexpiprazole, cariprazine, lumateperone), at least on theoretical grounds, may do more to increase prefrontal dopamine release as compared with D2 full antagonists, and in fact, meta-analyses have shown superiority for negative symptoms with most atypical antipsychotics over placebo, but not shown with as robust effects as one might hope. There are modest data, according to meta-analyses, using some antidepressants (of note, duloxetine, citalopram, fluvoxamine, mirtazapine, or selegiline) as adjunctive treatments specifically for negative symptoms. Stimulants such as lisdexamfetamine have some preliminary supportive data as adjuncts to antipsychotics, although findings from other studies of adjunctive dextroamphetamine or armodafinil have not been very compelling. Limited data also support the adjunctive use of the D2/D3 full dopamine agonist pramipexole added to antipsychotics, without worsening of positive symptoms.

In terms of residual positive symptoms, there are very limited data to support the combined use of different antipsychotics or adding mood stabilizers. Optimized or supratherapeutic dosing has not necessarily been shown to be more efficacious than standard dosing, with rare exceptions (eg, olanzapine dosing from 20-40 mg/day). The best data for antipsychotic combination therapy comes from adding a dopamine partial agonist such as aripiprazole to clozapine. As noted above, the option to add xanomeline-trospium to a non-anticholinergic antipsychotic may also be reasonable.

In terms of adverse effects, that is a vast topic depending on which adverse effect is of concern. Weight gain and metabolic dysregulation are usually best managed initially by introducing metformin dosed up to 2000 mg/day. Appetite stimulation can sometimes be managed with phentermine plus topiramate. GLP-1 agonists can be highly effective to counteract insulin resistance and promote weight loss and better glycemic control although it is far easier and preferable to minimize or prevent weight gain from occurring at the outset (eg, metformin cotherapy; favoring olanzapine/samidorphan over olanzapine; avoiding cotherapies that might add further to weight gain or appetite stimulation) than to reverse it once it has occurred. Sedation can sometimes be managed using adjunctive wakefulness-promoting agents (eg, [ar]modafinil or solriamfetol, and sometimes cautiously dosed stimulants), along with minimizing cotherapies that can further add to sedation (eg, sedative hypnotics, antihistamines/anticholinergics). TD is most effectively managed with VMAT2 inhibitors. Sexual dysfunction tends to respond best to switching to agents that are prolactin sparing and/or sometimes adding a phosphodiesterase inhibitor such as sildenafil.

When starting a patient on X/T, what practical tips can you share on titration and concomitant medications? In clinical practice, do you ever change the recommended titration schedule to improve tolerability or gain faster symptom control?
Ensuring that X/T is taken on an empty stomach is one component of minimizing nausea, as trospium otherwise has relatively poor absorption and bioavailability. Higher doses of X/T that involve a trospium dose of 30 mg twice daily may be especially useful in overriding nausea, so although gradual titrations are sometimes favored to allow acclimation, optimized dosing may actually provide a more favorable xanomeline component. I personally have never initiated treatment at doses higher than 50/20 mg twice daily, but prolonging the initiation dose phase longer than a few days may not necessarily help counteract nausea. Early, if not even prophylactic, use of ondansetron can also be helpful to prevent or mitigate nausea.

Whom do you see as an ideal candidate for X/T, and are there patient characteristics that would be red flags for use of this medication? What are your primary counseling points when you start someone on this medication?
Until there are data available in patients with schizophrenia and previous nonresponses to antipsychotics, it is premature to assume X/T has efficacy in treatment-resistant psychosis. I would also be cautious about tampering with the regimen of a patient with more difficult-to-treat schizophrenia but is stable while receiving clozapine (the only FDA-approved medication for treatment-resistant schizophrenia) unless adverse effects greatly outweighed benefits. We have no data regarding the effect of X/T on mood symptoms, and there is some research suggesting that procholinergic drugs could worsen depression, so there is a need for studies with X/T to address that question. X/T is a very reasonable treatment option for patients who are dissatisfied with current treatments, who have experienced significant weight gain or metabolic adverse effects, or who have involuntary movements (eg, TD) inasmuch as X/T has no ill effects on dopamine pathways in the dorsal striatum.

What are your thoughts about GLP-1s in patients with schizophrenia?
There are very compelling initial data to counteract weight gain and metabolic dysregulation, as well as alcohol craving and cardiovascular disease. This directly addresses the mechanism of overcoming iatrogenic insulin resistance as a contributor to antipsychotic-induced weight gain.

For patients who have a lot of nausea with X/T, would additional trospium be more useful rather than using ondansetron, since ondansetron does not really address the mechanism causing the nausea?
Probably yes. The maximum dose of trospium is 60 mg/day, as captured in the 125/30 mg twice-daily formulation of X/T. However, one must watch for excessive peripheral anticholinergic effects with maximum trospium dosing (eg, constipation, dry mouth, blurred vision, urinary retention) and be aware of any additive anticholinergic effects with other medications (eg, diphenhydramine, doxepin, tricyclics).

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