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Antipsychotics on Cognitive Impairment: Improve or Worsen?

Antipsychotics are the mainstay of treatment for psychotic disorders and are often used in the long term. It is thought that the improvement in cognitive impairment follows the improvement in psychotic symptoms.

However, available data indicate that cognitive impairment symptoms persist even though psychotic symptoms have improved. Several studies have also shown a risk of worsening cognitive impairment with the use of typical antipsychotics.

Meanwhile, there are reports that atypical antipsychotics have the potential to improve cognitive impairment. There is also a different opinion if the two antipsychotics, both typical and atypical, still cause worsening cognitive impairment. But some studies discuss that cognitive deterioration only occurs in certain genetic susceptibility which binds to certain antipsychotics.

Correlation Between Typical and Atypical Antipsychotics with Cognitive Impairments 

There is a theory that cognitive impairments in schizophrenic due to prefrontal cortex hypoactivity (PFC). These cognitive impairments are associated with specific symptoms in attention, working memory, and executive function.

a. Typical Antipsychotics 

Antipsychotics acting on the Dopamine 2 receptor antagonist are thought to reduce the hypodopaminergic state of the mesocortical pathway (projected to PFC). This exacerbates negative symptoms and cognitive impairment. Typical antipsychotics act as potent antagonists at D2 receptors. So, these drugs are often associated with more severe cognitive impairment than atypical antipsychotics.

b. Atypical Antipsychotics 

Several short-term studies have shown that atypical antipsychotics' use improves shifting ability, a component of cognitive flexibility.

Here are some atypical antipsychotic drugs and cognitive impairments:
  • Clozapine: provide (high level) improvement in attention and verbal fluency, but moderate improvement in executive function and delayed recall.
  • Olanzapine: significantly improves alertness, selective attention, delayed recall, memory and verbal learning, verbal fluency, and executive function.
  • Risperidone: improve working memory, executive function, attention, and delayed recall.
  • Aripiprazole: improve the speed of processing information accompanied by providing the correct response to a given stimulus. Including improvement in verbal cognitive function
  • Quetiapine: improve global cognitive function in the early stages of therapy and short-term verbal memory.

In 2016, Nielsen et al. conducted a meta-analysis that involved 37 randomized controlled trials (RCTs) to assess cognitive performance in schizophrenic or schizoaffective patients. Three thousand five hundred twenty-six schizophrenic or schizoaffective patients received atypical antipsychotics lasting eight weeks.

The mean use of antipsychotics was 23.6 weeks. Antipsychotics used were clozapine, olanzapine, risperidone, quetiapine, clozapine, ziprasidone, amisulpride, perospirone, and sertindole. This study showed mixed data, so it wasn't easy to conclude, but there were specific trends.

Nielsen et al. assessed that potent antagonists to muscarinic receptors would worsen attention and verbal working memory. The following drugs caused cognitive impairment worsening:

  1. Ziprasidone has weak binding to muscarinic receptors. It is better in verbal working memory than clozapine, olanzapine, and quetiapine.
  2. Sertindole has a positive effect on the executive function compared to clozapine, olanzapine, ziprasidone, and haloperidol.
  3. Sertindole and quetiapine both have improved information processing speed when compared to other atypical antipsychotics.
  4. Possible positive effects on verbal fluency are from the use of clozapine and olanzapine.

However, the results shown from the long-term impact on verbal memory and the visuospatial domain are mixed and difficult to conclude. Besides, no difference was found between motor function in the long-term use of atypical and typical antipsychotics. This is thought to be closely related to the dose and condition of polypharmacy.

Factors Affecting Cognitive

Several factors influence the relationship between the use of antipsychotics and cognitive impairment. Influencing factors include:

a. Clinical Symptoms Improvement

The use of typical and atypical antipsychotics is said to be both able to improve psychotic clinical symptoms (both negative and positive symptoms). Still, improvements do not necessarily follow these improvements in executive function. It is suspected that cognitive flexibility may be related to genetic abnormalities in people with psychotic disorders.

On the other hand, contradictory data states that cognitive improvement is correlated with improvement in psychotic symptoms. The improvement in negative symptoms coincided with an increase in information processing speed after 24 weeks of atypical antipsychotics.

b. Interference Phase and Duration

The data presented suggest that cognitive improvement was found with antipsychotics (both typical and atypical) in the first 1-2 years. Slight cognitive improvement after initiation of antipsychotics is thought to result from an improvement in psychotic symptoms. The improvements achieved also vary depending on the duration of the disturbance.

First episode psychotic patients who received antipsychotic therapy (with a duration < 3 months of disturbance) reported significant cognitive improvement. Improvement in this group was observed after 3 to 5 years of observation. Meanwhile, in chronic schizophrenia patients, relatively static results and no cognitive improvement were found within six months to 1 year of observation, although positive symptoms showed improvement.

c. Antipsychotic Dosage

Observations of accumulated antipsychotics' effects for approximately 16.5 years in 60 schizophrenic patients (and cognitive function assessments were performed at age 43 years) showed worsening cognitive scores. This worsening was not significantly different in the groups receiving atypical and typical antipsychotics, especially in verbal and memory learning. Higher cumulative antipsychotics were also associated with decreased brain mass.

Higher doses or antipsychotic polypharmacy were associated with poorer information processing speed. Meanwhile, the reduction in dose showed significant improvements in memory, visuospatial, language, attention, and delayed memory.

The presumed underlying mechanism is that high doses of antipsychotics will increase D2 occupation above 80%. This results in widespread dopamine blockade, including the mesocortical pathways associated with cognitive function. In addition, antipsychotics that act on histamine-1 receptors, muscarine, alpha-1-adrenergic, and 5-HT-2A (serotonin) antagonists have glutaminergic inhibiting effects, so they can interfere with mesolimbic and mesocortical functions.

d. Treatment Adherence

Schizophrenic patients who were adherent to treatment showed better cognitive improvements than those who regularly did not take antipsychotics.  A study compared oral risperidone and the long-acting injection (LAI) form and showed that white matter and myelination increased with LAI use and decreased with oral use. The mechanism underlying this is thought to be a more stable dose of LAI so that it does not increase D2 occupation above 80%.

e. Anticholinergic Side Effects

Extrapyramidal side effects (EPS) are said to be closely related to cognitive impairment, namely set-shifting, even in the absence of active antipsychotic therapy. The symptoms of bradykinesia and rigidity will also affect the grasping ability test, a cognitive test component.

In addition, in EPS, anticholinergic agents who have negative cognitive effects, are also often used. Impaired cognitive areas usually include attention and memory. Discontinuation of these anticholinergic agents has also been reported to improve cognitive function.

f. Side Effects of Metabolic Dysregulation

All antipsychotics had the side effect of metabolic dysregulation. And the highest proportion of atypic antipsychotics (i.e., olanzapine and clozapine).

In the non-psychiatric population (and not using antipsychotics), metabolic dysregulation is closely associated with worsening cognitive function. Cognitive domains that experience disability are memory, visuospatial, executive function, information processing speed, and intellectual function. These disorders are thought to result from insulin resistance, increased oxidative stress, and persistent inflammatory conditions.

g. Biological Factors

Endogenous Histone deacetylase 2 (HDAC2) activity plays a role in cognitive performance and synaptic plasticity (structural and functional). Chronic therapy with atypical antipsychotics (clozapine) has been associated with selective augmentation of HDAC2 transcription in the rat frontal cortex. This cortex deals with cognitive function and perception.

Ibi et al.'s molecular observation research used rats divided into several groups, namely, antipsychotics and controls. The groups that received antipsychotics were divided into several small groups, namely groups using clozapine, quetiapine, risperidone, haloperidol, sulpiride, and volinanserin. In the antipsychotic group, it was given continuously for 21 days (chronic).

The study aimed to assess the augmentation of HDAC2 expression in mice. This study showed a similar effect between atypical antipsychotics (especially clozapine and risperidone) and typical when used chronically, except for haloperidol on HDAC2 upregulation.

Augmentation of HDAC2 expression has a maladaptive effect on cortical synaptic remodeling and cognitive processes. The underlying mechanism is a signaling mechanism involving the upregulation of serotonin (5-HT2A) receptors -dependent on NF-KB (nuclear factor-kappaB) activity. In mice, this signaling activity will trigger psychosis-related behavior.


The first time use of both atypical and typical antipsychotics for the short term (1 to 2 years of treatment) is said to be equally able to improve cognitive function. Atypical antipsychotics are said to be better than typical, especially in improving shifting ability. This is presumably because the antagonist binding is not as strong as the typical antipsychotic at the D2 receptor. Strong binding to the D2 receptor itself is directly related to worsening negative symptoms and cognitive impairment.

Meanwhile, the long-term (chronic) use of atypical and typical antipsychotics did not significantly differ in worsening cognitive function. This is assessed by a decrease in brain volume and a decrease in cognitive function examination scores.

This cognitive activity is also influenced by other factors such as clinical symptoms that do not improve, the onset of more chronic disorders, large doses of antipsychotics or polypharmacy, poor medication adherence, sedation effects of antipsychotics, side effects of anticholinergics, side effects of metabolic disorders and augmentation of HDAC2.

Until now, the recommendations for how long antipsychotics can be used still vary, and data on the effects on cognitive function are still mixed. Until now, there are no recommendations regarding periodic cognitive examinations or recommendations for measuring cognitive function used in antipsychotic users. So, this article is expected to provide a separate understanding of the importance of observing cognitive function in the long-term use of antipsychotics.

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