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Switching Antipsychotic Medications in Schizophrenia: Why, When and How?

  • Typical and atypical antipsychotic medication can display varying effectiveness and adverse events in people living with schizophrenia. Monotherapy is normally preferred but combination options are possible. Switching to atypical antipsychotics from typical antipsychotics appears to be the most effective treatment change, and combination regimens can support the switch.

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Antipsychotic medication was introduced in the 1950s to reduce or alleviate psychotic episodes, such as visual or auditory hallucinations and delusions.1 Antipsychotics are mainly used to manage the positive symptoms of schizophrenia but their long-term use can be associated with treatment resistance or the appearance of adverse effects like involuntary movement disorders, tremor, drowsiness, metabolic and weight changes2,3.

Types of Antipsychotics

Typical antipsychotics, such as haloperidol and chlorpromazine, were the first to be produced and they are still useful in treatment when newer medications are ineffective.4 However, these medications do have a high risk of side effects, some of which can be quite severe.5 More specifically, they have been associated with extrapyramidal side-effects (EPS), a cluster of symptoms consisting of parkinsonism, dystonias, and akathisia.6 Side effects vary depending on the treatment agent. Apart from EPS, dry mouth, muscle stiffness and dyskinesia are also common adverse conditions linked to their use.4
In response to the serious side effects of many typical antipsychotics, atypical antipsychotics were developed. These newer medications were approved for use in the 1990s and they have become the drugs of choice for psychotic episodes.5 They are “atypical” as they are differentiated from “conventional” or first-generation antipsychotics based on their clinical profile and they are less likely to produce side effects.7 Atypical agents are generally safer to use, although some adverse events such as akathisia, metabolic changes and seizures might occur.5
With the discovery of clozapine in 1959, the first atypical antipsychotic approved for use,8 it became evident that this drug was less likely to produce EPS in humans at clinically effective doses than some other types of antipsychotics, and it has been widely available for decades as the only medication approved for treatment-resistant schizophrenia.9

Switch Strategy: Why?

The switch method, dose and strategy should be examined case by case and should take into account clinical trials and real clinical practice, such as observational studies. In case of an ineffective therapeutic scheme, the first change should include a gradual increase in dose to the upper limit of the licensed dose, if it is tolerable.3

Switch Strategy: When and How?

Switching antipsychotics can be considered in the following cases:12

Optimisation of antipsychotic dose and/or taking a medication for a long time has not resulted in clinical added benefit

A patient acutely relapses despite good medication adherence

Poor antipsychotic tolerability, such as cases when:

The antipsychotic dose cannot be lowered because of unacceptable risk of clinical worsening

A treatment-limiting adverse effect is unlikely to disappear at lower doses

Patient and/or caregiver request

Need to minimize medication cost or simplify dosing

Low treatment adherence

Antipsychotic switching can possibly be conducted two weeks after the initial antipsychotic starts13, however the exact timing remains an ongoing debate. Data from switching studies on schizophrenic patients with a poor response on antipsychotic monotherapy, showed comparable efficacy regarding positive and negative symptoms, but a drug-free period between discontinuing the first antipsychotic and starting the second is not recommended due to the risk of relapse.15 In particular, there are different methods of switching, listed on Table 1.15

Strategies for Switching Antipsychotics

StrategyDescriptionRisksHow to manage
Direct switchFirst antipsychotic is stopped and next one is started on the following day.
Simplest strategy.
Risk of discontinuation symptoms from first antipsychotic.
Significant risk of drug interactions.
Expertise required.
Consider individual drug characteristics. Should be avoided if possible when switching from clozapine.
Cross titrationFirst antipsychotic is gradually reduced, while second one is gradually increased to therapeutic dose.
Most common strategy used in clinical practice.
Provides some balance between minimising risk of relapse and minimising risk of adverse effects during overlap.
Possibility of drug interactions due to differing pharmacokinetics.Expertise required.
Continuation with slower titration and subsequent discontinuationFirst antipsychotic is continued at usual dose, second antipsychotic is gradually titrated up to near therapeutic dose, then first antipsychotic is gradually reduced and stopped, while dose of second one is increased to its therapeutic dose.
Most conservative strategy
Significant overlap of the two antipsychotics with a likelihood of adverse effects during switch.
Planned discontinuation of first antipsychotic may never takes place or therapeutic dose of second antipsychotic may not reached.
Restrict to patients with high risk of relapse.

Reference: Adapted from Keks, Schwartz and Hope. Aust Prescr. 42(5), 152–157 (2019)15

Studies have demonstrated that after switching there are no significant differences in any clinical outcomes, including tremor, dyskinesia, dizziness, extrapyramidal symptoms and treatment-emergent adverse events, between wait discontinuation (i.e. introducing the new antipsychotic while maintaining the first for a period before initiating its discontinuation) and non-wait discontinuation (i.e. initiating the first antipsychotic’s discontinuation when introducing the new antipsychotic), suggesting either strategy can be used in clinical practice. 16,17 Moreover, there is evidence that most individuals with schizophrenia or schizoaffective disorder currently receiving antipsychotic polypharmacy could be safely transitioned to antipsychotic monotherapy with no clinical deterioration, but that a minority of individuals benefit from antipsychotic polypharmacy.18
In the process of antipsychotic switching, transient polypharmacy is inevitable, as mentioned above. When the mental condition after the completion of antipsychotic switching becomes worse than that during transient polypharmacy, returning to the state of transient polypharmacy is the only option.19


  1. Ortiz‐Orendain et al. Cochrane Database Syst Rev. 2017; 2017(6): CD009005.
  2. Finkel et al. Pharmacology 2009; p.151-153
  3. Hatta et al. Ther Adv Psychopharmacol. 2018; 8(6): 173–183.
  4. Stevens et al. Psychiatry (Second Edition) 2011; p.24-25
  5. Mackin et al. BMJ 2011; 342
  7. Willner et al. StatPearls Publishing 2019; NBK448156
  8. Stroup et al. Am J of Psych 2016;173(2):166‐73
  10. Leucht et al. Lancet 2013; 382:951–962
  11. Taylor et al. Journal of Psychopharm 2000;14(4):409‐18
  12. [Accessed on 22nd November 2019]
  13. Samara et al. J Psychiatry. 2015; 172(7):617-29
  14. Zink et al. J Psychopharmacol 2008; 23(3):305-314
  15. Keks, Schwartz and Hope. Aust Prescr. 2019 Oct; 42(5):152–157
  16. Sajatovic et al. Ther Adv Psychopharmacol 2016; 6:355–368
  17. Takeuchi et al. Schizophr Res 2017; 189: 4–8
  18. Borlido et al. J Clin Psychiatry 2016; 77:e14–e20
  19. [Accessed on 22nd November 2019]
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The clinical efficacy profile of typical antipsychotic agents appears to depend on high affinity for and full antagonist activity at dopamine D2 receptors. Due The clinical efficacy profile of typical antipsychotic agents appears to depend on high affinity for and full antagonist activity at dopamine D2 receptors. Due


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