Antipsychotic drugs


Antipsychotics, are also known as neuroleptics.

A class of medication used to manage psychosis: delusions, hallucinations, paranoia or disordered thought, and schizophrenia,  but also in a range of other psychotic disorders.

Antipsychotics are a type of psychoactive or psychotropic medication.

Antipsychotic medications are the mainstay together with mood stabilizers in the treatment of bipolar disorder.

Antipsychotic medications associated associated with poor medication adherence and relapses of psychosis. 20-33% of patients do not have a response to conventional treatment, another’s have residual psychotic symptoms.

Antipsychotic drugs are associated with adverse events: extrapyramidal symptoms, sedation, weight gain, metabolic disturbances, gynecomastia, impotence, and hyperprolactinemia.

Long-term use can produce tardive dyskinesia.

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. 

First-generation antipsychotics, are known as typical antipsychotics.

Second-generation drugs, are known as atypical antipsychotics.

First and second generations of medications block receptors in the brain for dopamine, but atypicals tend to act on serotonin receptors as well. 

The second-generation antipsychotics are generally distinguishable by the presence of 5HT2A receptor antagonism and a corresponding lower propensity for extrapyramidal side effects compared to first-generation antipsychotics.

Antipsychotics are most frequently used for the following conditions:


Schizoaffective disorder most commonly in conjunction with either an antidepressant or a mood stabilizer.

Bipolar disorder (acute mania and mixed episodes) 

Psychotic depression

Antipsychotics approved for schizophrenia work primarily by antagonizing D 2 dopamine receptors.

Muscarinic system is also involved in the pathophysiology of schizophrenia.

Bipolar disorder may be treated with either typical or atypical antipsychotics.

Psychotic depression. 

Antipsychotics are generally not recommended for treating behavioral problems associated with dementia, or insomnia.

Evidence-based indications for using antipsychotics in children:  tic disorder, bipolar disorder, psychosis.

Such drug treatment is a key component of schizophrenia treatment, to reduce the symptoms of psychosis that include delusions and hallucinations. 

There is mixed evidence to support a significant impact of antipsychotic use on negative symptoms of apathy, lack of emotional affect, and lack of interest in social interactions or on the cognitive symptoms of memory impairment, reduced ability to plan and execute tasks.

The efficacy of antipsychotic treatment in reducing both positive and negative symptoms appears to increase with increasing severity of baseline symptoms.

All antipsychotic medications work by antagonizing D2 dopamine receptors. 

Atypical antipsychotic medications lower the neurocognitive impairment associated with schizophrenia more so than conventional antipsychotics.

Antipsychotic drug treatment of schizophrenia include:  prophylaxis in those at high risk of developing psychosis, treatment of first episode psychosis, maintenance therapy, maintenance therapy, and treatment of recurrent episodes of acute psychosis.

Patients with low-level psychotic symptoms and cognitive disturbances, combined with family history information to identify patients in a  high-risk group have a 20–40% risk of progression to frank psychosis within two years: treatment  with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis is appropriate.

There is, however, little evidence that early use of antipsychotics improves long-term outcomes in those with prodromal symptoms.

A first episode psychosis can treated with both an antipsychotic drug, and cognitive behavioral therapy (CBT): the combination treatment is more effective.

Only  60% of those presenting with a first episode psychosis will later be diagnosed with schizophrenia.

First episode drug induced psychosis conversion  to bipolar disorder or schizophrenia are lower, with 30% of people converting to either bipolar disorder or schizophrenia.

Clinical trials have provided evidence for the efficacy of antipsychotic drugs for first episode psychosis, with first-generation and second generation antipsychotics showing about equal efficacy. 

Early treatment of first episode psychosis having  a favorable effect on long term outcomes is equivocal.

Trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms.

The efficacy of antipsychotic drugs, including first and second generation agents, have little or no difference.

Antipsychotic drug efficacy is, however, sub optimal, and few patients achieve complete resolution of symptoms.

Response rates are low and their interpretation is complicated by high placebo responses.

There is selective publication of clinical trial results, obscuring results.

Patients generally experience a response within four weeks, and  continuing treatment  maintains suppression of symptoms, prevents relapse, improves quality of life, and supports engagement in psychosocial therapy.

While maintenance therapy with antipsychotic drugs is superior to placebo in preventing relapse, it is associated with weight gain, movement disorders, and high dropout rates.

With  maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction and achieved remission, and only 27% experienced satisfactory quality of life. 

Studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.

Maintenance therapy clearly reduces the rate of relapses requiring hospitalization.

A study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed antipsychotics prior to stopping therapy: If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalization compared to those that stopped taking antipsychotics.

Most patients who discontinue treatment do so because of suboptimal efficacy.

Antipsychotics in long-acting injectable depot form are used to ensure adherence in outpatient commitment.

Long-acting injectables result  in lower rates of rehospitalization.

Antipsychotics drugs routinely used, often in conjunction with mood stabilizers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder.

Antipsychotics have efficacy when used alone in acute mania/mixed episodes.

Three atypical antipsychotics: lurasidone, olanzapine and quetiapine have efficacy in the treatment of bipolar depression as a monotherapy.

Olanzapine and quetiapine have been proven to be effective against all three types of relapse—manic, mixed and depressive.

Cochrane review found olanzapine had a less favorable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.

Antipsychotics agents are recommended for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes.

Discontinuation by patients is associated with higher rates of relapse, including hospitalization.

Psychosis and agitation develop in as many 80 percent of people living in nursing homes.

There is a lack of FDA approval and black-box warnings for use of atypical antipsychotics are often prescribed to people with dementia.

Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a fairly large increase in serious adverse events. 

Antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others.

FDA has an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia.

Atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder.

Aripiprazole, quetiapine extended-release, and olanzapine have received approval for major depressive disorder.

There is, however, a greater risk of side effects with their use compared to using traditional antidepressants.

Antipsychotics may be used for obsessive–compulsive disorder, posttraumatic stress disorder, personality disorders, Tourette syndrome, autism,agitation in those with dementia, and treatment of impulse-behavioral and cognitive-perceptual symptoms of borderline personality disorder.

Evidence does not support the use of atypical antipsychotics in eating disorders or personality disorder.

Atypical risperidone may be used in management of obsessive–compulsive disorder.

The use of antipsychotics for insomnia, is not recommended as there is little evidence of benefit and concerns regarding adverse effects.

In children antipsychotics may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.

Antipsychotics are recommended for Tourette syndrome, although they are effective side effects are common.

Risperidone and aripiprazole have been approved for the treatment of irritability in autistic children and adolescents.

In aggressive behavior of ADHD, and other patterns of aggressive behavior antipsychotic agents are an option.

Antipsychotics are not been found to be useful for the prevention of delirium among those admitted to hospital.

Whether the atypical, second-generation, antipsychotics offer advantages over older, first generation antipsychotics remains controversial.

Second generation antipsychotics

may be more effective but are associated with greater side effects.

However, typical antipsychotics have equal drop-out and symptoms rates to atypicals when used at low to moderate dosages.

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.

There is a significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and some recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter.

More than one antipsychotic drug should not be used at a time because of increased adverse effects.

Common adverse effects of antipsychotics include:






Extrapyramidal side effects:particularly common with first-generation antipsychotics which include:

Akathisia, an often distressing sense of inner restlessness.

Dystonia, an abnormal muscle contraction


Hyperprolactinaemia : 



Sexual dysfunction


Orthostatic hypotension

Weight gain 

Anticholinergic side-effects 

Blurred visionConstipation

Dry mouth 

Reduced perspiration

Tardive dyskinesia

Rare/Uncommon (<1%)  effects of antipsychotics include:

Blood dyscrasias 

Metabolic syndrome and other metabolic problems.

Females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.

Metabolic adverse effects appear to be mediated by weight gain by antagonizing the histamine H1 and serotonin 5-

 HTC2/receptors and perhaps by interacting with other neurochemical pathways in the central nervous system.

Neuroleptic malignant syndrome


QT interval prolongation

Torsades de pointes



Myocardial infarction


Some studies have found decreased life expectancy associated with the use of antipsychotics: dementia.

High doses of antipsychotic drugs are usually no more effective but is usually more harmful.

Loss of grey matter and other brain structural changes over time are observed with schizophrenia. 

The effects of antipsychotic treatment on grey matter volume and the brain’s structure are controversial.

A gradual discontinuance of   antipsychotic drugs is recommended to avoid acute withdrawal syndrome or rapid relapse.

Symptoms of antipsychotic drug withdrawal commonly include.: nausea, vomiting, and loss of appetite, restlessness, increased sweating, and trouble sleeping, numbness, or muscle pains.

Withdrawal symptoms generally resolve after a short period of time.

Discontinuation of antipsychotics can result in psychosis, and recurrence of the condition.

Rarely tardive dyskinesia can occur when an antipsychotic drug  is stopped.

When switching a person from one antipsychotic to another, withdrawal effects may also occur.

Adverse effects of switching antipsychotics are more likely during rapid changes,  and gradual change between antipsychotics minimizes these withdrawal effects.

The long-term exposure to prolactin-increasing antipsychotics is associated with a 56% increased risk of developing breast cancer

Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D2 receptors in the dopaminergic pathways of the brain. 

Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. 

Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder.

Antipsychotics, in particular atypical neuroleptics, also antagonize 5-HT2A receptors. 

Antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. 

Blocking D2 receptors produce some unwanted side effects that the typical antipsychotics.

Atypical antipsychotic drugs have a similar blocking effect on D2 receptors, but most also act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. 

5-HT2A antagonism increases dopaminergic activity leads to a lowered extrapyramidal side effect liability among the atypical antipsychotics.

They may be administered orally or, in some cases, by long-acting injections.

Short-acting parenteral formulations are generally reserved for emergencies or when oral administration is otherwise impossible. 

The oral formulations include immediate release, extended release, orally disintegrating products,

and sublingual.

Second-generation antipsychotics are misused or abused for their sedative, tranquilizing, and hallucinogenic effects: most commonly second-generation antipsychotic implicated is quetiapine.

Dementia patients taking antipsychotics have increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality.

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