Switching antipsychotics?

Sometimes, slower isn’t safer.

This is Part 3 in my A-to-Z series from the upcoming 8th edition of the Med Fact Book.

Today: Antipsychotics.

We switch them for all kinds of reasons—side effects, partial response, patient preference.

And most of us default to a cross-taper—gradually tapering the old drug while titrating up the new one.

It feels safer. More measured.

But often those careful cross-tapers stall—and our patients end up on both meds longer than intended.

Polypharmacy creeps in, and inertia takes over.

So here’s an interesting data point to consider:

A large meta-analysis (n = 1,400+) found no clear benefit to gradual switching.

Immediate switches were just as effective—and often better tolerated. (Takeuchi et al, Schiz Bull, 2017)

So when should you not cross-taper—and what should you do instead?

▸ When both meds are sedating

Example: olanzapine to quetiapine

Cross-tapering stacks sedation and orthostatic risk—some patients feel like they’re falling asleep while standing up.

Instead: Taper the first drug down to a lower dose (or off) before starting the new one. A brief gap is often safer than an overlap.

▸ When one’s a partial agonist and the other’s a full antagonist

Example: risperidone to aripiprazole

Aripiprazole partially stimulates dopamine receptors, while risperidone blocks them.

During overlap, aripiprazole can displace risperidone and unmask dopamine activity—agitation, insomnia, restlessness.

Instead: Taper or stop the antagonist first, then introduce aripiprazole once symptoms are stable. Avoid overlap to prevent pharmacodynamic push-pull.

▸ When overlapping leads to additive side effects

Example: quetiapine to olanzapine

→ double sedation, weight gain, metabolic burden

Risperidone to paliperidone

→ excessive prolactin elevationInstead: Use a sequential switch—reduce or stop the first agent before starting the second. If overlap is needed, keep it short and at the lowest effective doses.

▸ When switching to clozapine

Clozapine titration takes time—and therapeutic levels often start around 300–400 mg/day.

Tapering the previous antipsychotic too early risks destabilization.

Instead: Start clozapine while maintaining the current antipsychotic.

Once clozapine reaches a clinically effective dose, then taper off the first med. It's a deliberate lead-in, not a true cross-taper.

These are the kinds of clinical detours that don’t always make it into guidelines.

Cross-tapering makes sense—until it doesn’t.

Next up: Deprescribing antipsychotics—and why that’s often harder than starting them.

▸ Follow me (Daniel Carlat, MD) for grounded psychopharm tips from the Med Fact Book 

▸ What antipsychotic switch has caught you off guard?

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