Nearly 70 years ago, the discovery of the antipsychotic activity of chlorpromazine and its clinical success in patients with psychosis expanded worldwide treatment.1 This discovery prompted researchers to shift their understanding of synaptic transmission from an electrical mechanism to a chemically mediated mechanism.2 Together, these findings led to the development of many new antipsychotics.

The first antipsychotics developed were termed first-generation antipsychotics (FGAs), or typical antipsychotics. The mechanism of action for FGAs is dopamine D2 neuroreceptor blockade. FGAs are divided into low, medium, and high-potency based upon binding affinity for the dopamine D2 neuroreceptor.

The later developed antipsychotics developed were named second-generation antipsychotics (SGAs), or atypical antipsychotics. The mechanism of action for SGAs is dopamine D2 neuroreceptor blockade, along with serotonin 5-HT2A neuroreceptor blockade.3

See Table I for a comprehensive list of FGAs and SGAs used in practice. (See also, finding the right antipsychotic treatment on our Psycom consumer site.)

The most common conditions antipsychotics are used to treat include schizophrenia, acute agitation, and bipolar disorder. They are also used as adjunctive therapy with antidepressants in major depressive disorder (MDD, see more on depression assessment).3 Research has demonstrated similar efficacy between FGAs and SGAs,4,5 with the possible exception of clozapine.6

 

Table I: Available First and Second Generation Antipsychotics – Common Uses and Warnings.7

Generic Name

(Brand Name)

Indication(s)

Boxed Warning(s)

 

FIRST-GENERATION ANTIPSYCHOTICS

Chlorpromazine

(Thorazine)

Agitation/aggression associated with psychiatric disorders, behavioral problems, bipolar disorder, hiccups (prolonged or intractable), hyperactivity, tetanus, schizophrenia

Off-Label: migraine, nausea & vomiting of pregnancy

Increased mortality in elderly patients with dementia-related psychosis

Fluphenazine

(Prolixin)

Psychotic disorders

Off-Label: chorea of Huntington disease, chronic tic disorders

Increased mortality in elderly patients with dementia-related psychosis

Haloperidol

(Haldol)

Behavioral disorders (nonpsychotic), hyperactivity, schizophrenia, Tourette syndrome

Off-Label: agitation/aggression associated with psychiatric disorders, bipolar disorder, chemotherapy-induced nausea & vomiting, delirium

Increased mortality in elderly patients with dementia-related psychosis

Loxapine

(Loxitane)

Schizophrenia, agitation associated with schizophrenia or bipolar 1 disorder Increased mortality in elderly patients with dementia-related psychosis; Bronchospasm (Adasuve inhalation product)

Perphenazine

(Trilafon)

Nausea & vomiting, schizophrenia Increased mortality in elderly patients with dementia-related psychosis

Thioridazine

(Mellaril)

Schizophrenia Increased mortality in elderly patients with dementia-related psychosis; Proarrhythmic effects

Thiothixene

(Navane)

Schizophrenia Increased mortality in elderly patients with dementia-related psychosis

Trifluoperazine

(Stelazine)

Schizophrenia Increased mortality in elderly patients with dementia-related psychosis
SECOND-GENERATION ANTIPSYCHOTICS

Aripiprazole

(Abilify)

Bipolar disorder, irritability associated with autistic disorder, major depressive disorder, schizophrenia, Tourette disorder

Off-Label: agitation/aggression associated with psychiatric disorders, delusions, chorea of Huntington disease, obsessive-compulsive disorder, psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis; Suicidality and antidepressant drugs

Asenapine

(Sephris)

Bipolar disorder, schizophrenia

Off-Label: agitation/aggression associated with psychiatric disorders, psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis

Brexpiprazole

(Rexulti)

Major depressive disorder, schizophrenia

Off-Label: psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis; Suicidal thoughts and behaviors

Cariprazine

(Vraylar)

Bipolar disorder, schizophrenia

Off-Label: major depressive disorder, psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis; Suicidal thoughts and behaviors

Clozapine

(Clozaril)

Schizophrenia, suicidal behavior in schizophrenia and schizoaffective disorder

Off-Label: bipolar disorder, psychosis/agitation associated with dementia, psychosis in Parkinson disease

Increased mortality in elderly patients with dementia-related psychosis; Severe neutropenia; Orthostatic hypotension, bradycardia, syncope; Seizures; Myocarditis, cardiomyopathy, and mitral valve incompetence

Iloperidone

(Fanapt)

Schizophrenia

Off-Label: psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis

Lurasidone

(Latuda)

Bipolar disorder, schizophrenia

Off-Label: major depressive disorder

Increased mortality in elderly patients with dementia-related psychosis; Suicidal thoughts and behaviors

Olanzapine

(Zyprexa)

Agitation/aggression associated with psychiatric disorders, bipolar disorder, major depressive disorder, schizophrenia

Off-Label: psychosis/agitation associated with dementia, anorexia nervosa, nausea & vomiting, delirium, delusions, chorea of Huntington disease

Increased mortality in elderly patients with dementia-related psychosis; Post-injection delirium/sedation (Zyprexa Relprevv)

Paliperidone

(Invega)

Schizophrenia, schizoaffective disorder

Off-Label: bipolar disorder, delusions, psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis

Quetiapine

(Seroquel)

Bipolar disorder, major depressive disorder, schizophrenia

Off-Label: psychosis/agitation associated with dementia, delirium, delusions, generalized anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, psychosis in Parkinson’s disease

Increased mortality in elderly patients with dementia-related psychosis; Suicidal thoughts and behaviors

Risperidone

(Risperdal)

Bipolar disorder, schizophrenia, irritability associated with autistic disorder

Off-Label: agitation/aggression associated with psychiatric disorders, agitation/aggression associated with dementia, delusions, chorea of Huntington disease, major depressive disorder, obsessive-compulsive disorder, Tourette syndrome

Increased mortality in elderly patients with dementia-related psychosis

Ziprasidone

(Geodon)

Agitation/aggression associated with psychiatric disorders, bipolar disorder, schizophrenia

Off-Label: agitation/delirium (intensive care unit), delusions, major depressive disorder, psychosis/agitation associated with dementia

Increased mortality in elderly patients with dementia-related psychosis

Data based on Reference 7.

Antipsychotic Prescribing Considerations

Individual approaches need to be the priority when considering which antipsychotic to prescribe. Factoring into any decision per the American Psychiatric Association’s guideline should be: patient preference, prior treatment response, adherence history, relevant medical history, risk factors, medication adverse effect profile, long-term treatment planning, and cost factor.6

Due to the high binding affinity for the dopamine D2 neuroreceptor, typical antipsychotics or FGAs are known to cause extrapyramidal dysfunction and hyperprolactinemia at higher rates than their atypical or SGA counterparts. Common extrapyramidal dysfunctions experienced by patients include acute dystonia, akathisia, pseudoparkinsonism, and tardive dyskinesia. Extrapyramidal dysfunction occurs most frequently with haloperidol, fluphenazine, and thiothixene.6,8

Due to binding affinity to multiple serotonin 5-HT receptors, SGAs are known to cause metabolic adverse effects at higher rates than FGAs. Common metabolic adverse effects are weight gain and hyperglycemia.  Metabolic adverse effects occur most frequently with olanzapine and clozapine.8

For patients in which cost is a factor for deciding an antipsychotic, FGAs may be more cost-effective due to the generic status of most medications.8 Lastly, special considerations are warranted for children and adolescents, pregnant patients, and adults over age 65.3

See also, how pharmacogenetic testing can help to target depression treatment with personalized antidepressants.  Plus, find additional antipsychotic prescribing considerations for treating patients with comorbid chronic pain on our sister site, PPM.

Antipsychotic Safety & Monitoring

Adverse effects for each medication can likely be predicted based on the receptor binding profile. For instance:

  • Receptor antagonism on serotonin 5-HT2C, histamine H1, dopamine D2, and receptor agonism on serotonin 5-HT1A have been associated with weight gain.
  • Receptor antagonism on serotonin 5-HT2C, histamine H1, and muscarinic M3 has been associated with hyperglycemia.
  • Extrapyramidal symptoms (EPS) and endocrine effects have been associated with receptor antagonism on the dopamine D2
  • Sedation has been associated with receptor antagonism on the histamine H1
  • Anticholinergic adverse effects have been associated with receptor antagonism on the muscarinic M19

Clinicians should consider the adverse effect profile of specific antipsychotics in relation to the patient’s clinical risks prior to prescribing.

Specific potential adverse effects for first-generation psychotics include EPS, dyslipidemia, neuroleptic malignant syndrome (NMS), prolonged QT interval, sexual dysfunction, seizures, and weight gain. Potential adverse effects for second-generation antipsychotics include NMS, postural hypotension, prolonged QT interval, sedation, sexual dysfunction, seizures, and weight gain.10 See Table II for individual antipsychotic adverse effect profiles.

Ongoing monitoring is recommended for all patients taking antipsychotics. Drug class monitoring parameters are fasting glucose and HbA1c, weight changes, blood pressure, fasting lipid panels, and ongoing adverse effects.3 Individual medication monitoring parameters should be determined prior to initiating treatment.

 Table II: Relative Risk of Adverse Effects of First and Second Generation Antipsychotics.6

                                                             RISKS FOR DEVELOPING CONDITIONS NOTED
Generic Name Parkinsonism Tardive Dyskinesia Orthostasis QT Prolongation Weight Gain Glucose Abnormalities
FIRST-GENERATION ANTIPSYCHOTICS
Chlorpromazine Medium High High High Medium Medium
Fluphenazine High High Low Medium Medium Low
Haloperidol High High Low Medium Medium Low
Loxapine Medium Medium Medium Medium Low Low
Perphenazine Medium Medium Medium Medium Medium Low
Thioridazine Low Low High High Medium Low
Thiothixene High High Low Medium Low Low
Trifluoperazine Medium Medium Low Medium Medium Low
 SECOND-GENERATION ANTIPSYCHOTICS
Aripiprazole Low Low Low Low Low Low
Asenapine Low Medium Medium Medium Medium Medium
Brexpiprazole Low Low Low Medium Low Low
Cariprazine Low Low Low Medium Medium Low
Clozapine Low Low High Medium High High
Iloperidone Low Low High High Medium Medium
Lurasidone Medium Medium Low Low Low Medium
Olanzapine Medium Low Medium Medium High High
Paliperidone Medium Medium Medium Medium Medium Low
Quetiapine Low Low Medium Medium Medium Medium
Risperidone Medium Medium Medium Medium Medium Medium
Ziprasidone Low Low Medium High Low Low

Data based on Reference 6.

How to Discontinue Antipsychotics

Discontinuing and switching antipsychotics generally occurs due to clinical ineffectiveness or intolerability and warrants precaution. Cholinergic rebound may occur due to a decreased activity on cholinergic receptors. Patients may experience a range of symptoms, including: nausea, vomiting, restlessness, anxiety, insomnia, fatigue/malaise, myalgia, diaphoresis, rhinitis, paresthesia, gastrointestinal distress, headaches, and nightmares.

Dopaminergic syndrome may also occur due to decreased activity on dopaminergic receptors. The clinical manifestations of this dopaminergic syndrome are withdrawal dyskinesias, akathisia, dystonia, and tardive dyskinesia. Rebound psychosis may also occur. Thus, it is recommended to taper all antipsychotics over weeks to months to limit these effects.11

Full Overlap, Partial Overlap, and Immediate Withdrawal

Risk of destabilization or relapse, worsened physical condition, discontinuation reactions, and NMS need to be considered when switching antipsychotic medications as well.12 Recommended approaches (via DynaMed) for changing medications are full overlap, partial overlap, and immediate withdrawal from the current medication and start of the new medication, each described briefly below.

Table III: Advantages and Disadvantages of Medication Change Approaches.3

Advantages Disadvantages
Full overlap
  • low risk of discontinuation effects and disease relapse
  • potential for increased adverse effects, drug interactions, and adherence issues
Partial overlap
  • lower risk for cholinergic rebound
  • time to assess new adverse effects
  • useful for switching from high potency FGAs to an SGA
  • potential for increased adverse effects, drug interactions
  • higher risk for disease relapse
  • potential for adherence issues
Immediate withdrawal and new start
  • low risk for medication errors
  • decreased potential for drug interactions
  • higher risk for discontinuation effects and disease relapse

FGA is a first-generation or typical antipsychotic. SGA is a second-generation or atypical antipsychotic.
Based on data from Reference 3. 

Additional Information on Prescribing and Changing Antipsychotics

The American Psychiatric Association’s Work Group on Psychiatric Evaluation issued Practice Guidelines for the Psychiatric Evaluation of Adults in 2015, excerpted here. Below are a few clinical takeaways from that work group and other association work group guidelines as cited.

 Consider the patient’s mood, level of anxiety, thought content and process, perception, cognition, and trauma history for the initial psychiatric evaluation.12

  • Consider creating a long-term treatment plan upon diagnosis of a psychiatric disorder.12
  • Explain to every patient the differential diagnosis, risks of untreated illness, treatment options, and benefits and risks of treatment.12
  • Don’t prescribe antipsychotics to patients for any indication without appropriate initial evaluation and appropriate ongoing monitoring.12
  • Don’t use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia.13
  • Don’t prescribe antipsychotic medications as first-line intervention for insomnia in adults.14
  • Don’t prescribe antipsychotics as monotherapy in patients with depression.15

For patients with schizophrenia, the association’s Practice Guideline for the Treatment of Patients with Schizophrenia – updated in 2020 – further advises:

  • All patients with schizophrenia should have an evidence-based and patient-centered treatment plan in place that includes both nonpharmacological and pharmacological treatments.6
  • Don’t routinely prescribe two or more antipsychotics concurrently.6

See also, a recent literature review on medication management for schizophrenia and bipolar disorder.

Atypical and Typical Antipsychotic Conclusions

In conclusion, an individual approach to each patient is recommended when using antipsychotics as part of a treatment plan. First- and second-generation antipsychotics differ in their mechanism of action, receptor binding profiles, approved indications, safety profiles, and cost.

Monitoring parameters should be assessed prior to initiating any antipsychotic. Special consideration needs to be taken when considering discontinuing and switching antipsychotics. Lastly, these medications are not without safety concerns and treatment decisions should be tailored case by case.

References
Last Updated: Sep 1, 2021