Antipsychotic switching refers to the process of switching out one

antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

for another antipsychotic. There are multiple indications for switching antipsychotics, including inadequate

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...

and

drug intolerance Drug intolerance or drug sensitivity refers to an inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses. Conversely, a patient is said to be "tolerating" a drug when they can tolerate its adve ...

. There are several strategies that have been theorized for antipsychotic switching, based upon the timing of discontinuation and tapering of the original antipsychotic and the timing of initiation and titration of the new antipsychotic. Major

adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

from antipsychotic switching may include supersensitivity syndromes,

withdrawal Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * ''Coitus interruptus'' (the withdrawal method) * Drug withdrawal * Social withdrawal * Taking of money from a ban ...

, and rebound syndromes.

Rationale

Antipsychotics may be switched due to inadequate efficacy,

, patient/guardian preference, drug regimen simplification, or for economic reasons. # Inadequate efficacy: An inadequate treatment response to an antipsychotic, assuming that the lack of efficacy is due to an otherwise adequately dosed regimen for an appropriate duration, can result from failure to achieve therapeutic goals in any major treatment domain. For example, this can refer to a patient who becomes acutely psychotic after being stable previously. Other failures include persistent symptoms of schizophrenia, either positive or negative, problems with mood (including suicidality), or problems with cognition. Inadequate efficacy may be due to nonadherence to therapy, which can influence treatment decisions. For example, long acting injectable (LAI)

antipsychotics Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

are often indicated in the setting of medication nonadherence. #

Drug intolerance Drug intolerance or drug sensitivity refers to an inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses. Conversely, a patient is said to be "tolerating" a drug when they can tolerate its adve ...

: Adverse effects can contribute to drug intolerance, potentially necessitating antipsychotic switching. Adverse effects that threaten serious harm, aggravate other medical conditions, or make a person want to stop taking their medications are all examples of drug intolerance. Certain

drug interactions Drug interactions occur when a drug's mechanism of action is disturbed by the concomitant administration of substances such as foods, beverages, or other drugs. The cause is often the inhibition of the specific receptors available to the drug, ...

can cause adverse effects as well. # Patient/guardian preference: A patient or caregiver may prefer a different antipsychotic. This may be due to misinformation regarding the antipsychotic, including its side effects, a lack of insight into the importance of the medication and the severity of the disease, or overestimating the therapeutic effect. # Drug regimen simplification: Adherence to medication therapy is inversely related to the frequency of dosing. The antipsychotic

quetiapine Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its ...

is typically dosed two to three times daily for the management of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

. A simpler regimen would be a once daily administered antipsychotic. For example,

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions ...

can be administered once daily. A lack of adherence can lead to poor health outcomes, as well as unnecessary financial burden. #

Economics Economics () is the social science that studies the Production (economics), production, distribution (economics), distribution, and Consumption (economics), consumption of goods and services. Economics focuses on the behaviour and intera ...

: A patient or caregiver may request antipsychotic switching to reduce medication costs. See below for a table of the direct costs of living with schizophrenia per patient across countries. ::

Contraindications

In general, contraindications to antipsychotic switching are cases in which the risk of switching outweighs the potential benefit. Contraindications to antipsychotic switching include effective treatment of an acute psychotic episode, patients stable on a LAI antipsychotic with a history of poor adherence, and stable patients with a history of

self-injurious behavior Self-harm is intentional behavior that is considered harmful to oneself. This is most commonly regarded as direct injury of one's own skin tissues usually without a suicidal intention. Other terms such as cutting, self-injury and self-mutilatio ...

violent behavior Violence is the use of physical force so as to injure, abuse, damage, or destroy. Other definitions are also used, such as the World Health Organization's definition of violence as "the intentional use of physical force or power, threatened o ...

, or significant

self-neglect Self-neglect is a behavioral condition in which an individual neglects to attend to their basic needs, such as personal hygiene, appropriate clothing, feeding, or tending appropriately to any medical conditions they have. More generally, any lack ...

or other symptoms.

Strategies

There are multiple strategies available for switching antipsychotics. An abrupt switch involves abruptly switching from one antipsychotic to the other without any titration. A cross-taper is accomplished by gradually discontinuing the pre-switch antipsychotic while simultaneously up-titrating the new antipsychotic. An overlap and discontinuation switch involves maintaining the pre-switch antipsychotic until the new antipsychotic is gradually titrated up, then gradually titrating down on the pre-switch antipsychotic. Alternatively, in an ascending taper switch, the pre-switch antipsychotic can be abruptly discontinued. Another alternative, known as the descending taper switch, involves slowly discontinuing the pre-switch antipsychotic while abruptly starting the new antipsychotic. These switching strategies can be further subdivided by the inclusion or exclusion of a plateau period. See the figure below for a graphic visualization of the five main antipsychotic switching strategies discussed above. Antipsychotic Switching Diagram

Due to differences in how individual antipsychotics work, even within each

generation A generation refers to all of the people born and living at about the same time, regarded collectively. It can also be described as, "the average period, generally considered to be about 20–⁠30 years, during which children are born and gr ...

, the process of switching between antipsychotics has become more complex.

Adverse effects

The three major adverse effects of antipsychotic switching are supersensitivity syndromes,

, and rebound syndromes.

Supersensitivity syndromes

Antipsychotics work by antagonizing the

dopamine receptor D2 Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, in ...

(D2R) in the

mesolimbic pathway The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral ...

of the brain. When the D2R is suppressed, the neurons may become sensitized to the effect of an

endogenous ligand In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...

(i.e.

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

) by up-regulating the production of

postsynaptic Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous sys ...

D2Rs. If the D2 receptors are not subsequently suppressed at previous levels after an abrupt discontinuation of an antipsychotic (e.g. after switching to weak D2R antagonists

clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...

), a rebound/supersensitivity

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

may occur due to the overwhelming effect of endogenous dopamine on sensitized neurons. Supersensitivity psychosis, also called rapid-onset psychosis, must be distinguished from a relapse or exacerbation of the underlying disease (e.g.

Dopamine supersensitivity psychosis Dopamine supersensitivity psychosis is a hypothesis that attempts to explain the phenomenon in which psychosis (e.g. having hallucinations, which can mean hearing or seeing things that other people do not see or hear) occurs despite treatment with ...

generally occurs around 6 weeks after an oral antipsychotic is discontinued, or 3 months after a LAI antipsychotic is discontinued. In addition, supersensitivity psychosis is generally easier to reverse by reintroducing D2R antagonism (i.e. restarting the discontinued drug), whereas a relapsed schizophrenia is more difficult to control.

Rebound syndromes

The second-generation antipsychotic

olanzapine Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is ta ...

is thought to have a rebound-induced

hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...

, which may be mediated by

serotonin receptors 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neur ...

. Hyperthermia, or elevated core body temperature, is associated with

neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fas ...

, a potentially lethal syndrome that commonly occurs due to excessive D2R antagonism. In general, rebound D2R activity may induce rebound

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...

and rebound

akathisia Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back and ...

Withdrawal

D2 receptor activity withdrawal may induce withdrawal

dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...

. This late-onset, hypersensitivity-type dyskinesia is in contrast to the early-onset dyskinesia that can occur due to an over-compensatory dopamine release associated with abrupt dopamine antagonist withdrawal. Other symptoms of dopamine withdrawal include

difficulty sleeping Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, and restlessness.

Alternatives

An alternative to antipsychotic switching, in the setting of a person that is not responding to the initial dose of an antipsychotic, is to increase the dose of antipsychotic prescribed. A 2018 Cochrane review compared the evidence between the two strategies, but the authors were unable to draw any conclusions about whether either method was preferable due to limited evidence.

Notes

References

{{reflist, 30em * Psychiatry controversies