Antipsychotic use during pregnancy requires careful consideration of the mother’s risk of illness relapse, against the risk of harm or complications for the mother and developing infant if medication is to be continued.

What is the evidence for the use of antipsychotics during pregnancy and breastfeeding?

High quality evidence finds a small, increased risk of gestational diabetes mellitus during pregnancy with antipsychotic use (first or second generation).

Moderate quality evidence suggests a small increased risk of heart defect or lower birth weight in infants, and a small increased risk of preterm delivery, but not stillbirth, with exposure to antipsychotics. Lower quality evidence is unsure about the risk of termination or spontaneous abortion, and the size and malformation in infants.

Review authors report that the studies did not routinely adjust for potential confounding factors, such as other medication use.

October 2020

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One-quarter to one-half of people with schizophrenia do not adhere to their medication. Non-adherence to maintenance treatments, including antipsychotics, is a widespread issue that plagues clinical management for schizophrenia. It reduces the success of the treatment regimen and the ability to achieve remission from illness, but it also increases the burden for psychotic relapse treatments, emergency admissions and hospitalisation. Greater adherence to treatment can contribute not only to more successful disease management and better quality of life, but also to improved attitudes towards treatment and medication, as well as increasing insight and confidence. In controlled clinical trials, drop-out rates can be a proxy measure of the overall tolerability and efficacy of the medication.

What is the evidence for medication adherence?

High quality evidence shows a small to medium-sized effect of lower drop-out rates in trials of flexible dose, second-generation antipsychotics compared to flexible dose, first-generation antipsychotics, with no differences in drop-out rates in trials of fixed doses. Moderate to high quality evidence suggests olanzapine and risperidone showed similar treatment response rates, but olanzapine had lower dropout rates. Moderate quality evidence suggests drop-out rates may be higher in people receiving placebo or first-generation antipsychotics compared to second-generation antipsychotics. Drop-out rates may increase with longer treatment duration.

For specific antipsychotics compared to placebo, moderate to high quality evidence shows there was less all-cause discontinuation with (in order of descending effects, first being best); clopenthixol, amisulpride, olanzapine, paliperidone, thiotixene, thioridazine, clozapine, loxapine, iloperidone, perphenazine, aripiprazole, risperidone, zuclopenthixol, zotepine, asenapine, quetiapine, lurasidone, brexpiprazole, haloperidol, and ziprasidone. There were no differences between placebo and perazine, levomepromazine, flupentixol, molindone, fluphenazine, chlorpromazine, cariprazine, sulpiride, sertindole, penfluridol, trifluoperazine, and pimozide.

October 2020

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Childhood-onset schizophrenia is defined as schizophrenia with onset prior to the age of 13 years, and early-onset schizophrenia describes schizophrenia onset between the ages of 13 and 17 years.

What is the evidence for pharmaceutical treatments for childhood and early-onset schizophrenia?

Compared to first-generation antipsychotics, moderate quality evidence finds a small to medium-sized benefit of second-generation antipsychotics for global and mental state in children and adolescents with schizophrenia. There was greater improvement with standard dose than low-dose antipsychotics, although there are more side effects with standard doses.

Moderate quality evidence finds clozapine was the most effective antipsychotic and fluphenazine was the least effective antipsychotic for symptoms when compared to placebo and other antipsychotics (ziprasidone, loxapine, trifluperazine, asenapine, haloperidol, quetiapine, paliperidone, aripiprazole, risperidone, lurasidone, olanzapine, or molindone). There were few significant differences between the other antipsychotics, with only ziprasidone being less effective for symptoms than olanzapine, molindine and risperidone.

For positive symptoms in particular (e.g. hallucinations and delusions), moderate to high quality evidence finds medium-sized improvements with olanzapine, risperidone, and asenapine, and small improvements with quetiapine, aripiprazole, and paliperidone over placebo. For negative symptoms (e.g. social withdrawal), moderate to low quality evidence finds medium-sized improvements with aripiprazole, asenapine, molindone, olanzapine and risperidone over placebo.

For side effects, moderate quality evidence finds haloperidol, loxapine, risperidone and quetiapine resulted in the most extrapyramidal (movement) symptoms. Olanzapine showed the most weight gain, followed by clozapine, quetiapine, paliperidone, risperidone, asenapine and then aripiprazole. There was less weight gain with lurasidone than with olanzapine, quetiapine, risperidone, asenapine, and paliperidone. Clozapine showed the most sedation, followed by paliperidone, asenapine, loxapine, olanzapine, haloperidol, aripiprazole, and risperidone. Risperidone showed the most prolactin increase, followed by haloperidol, olanzapine, paliperidone, and quetiapine.

October 2020

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Cognitive symptoms of schizophrenia have been found in all cognitive domains, including executive function, memory, and attention, and often develop prior to the other symptoms of schizophrenia. They are highly disabling and predict poor functional outcomes.

What is the evidence for treatments for cognitive symptoms?

Overall, moderate to high quality evidence suggests second-generation antipsychotics are associated with small improvements in processing speed, verbal fluency, learning, motor skills, long-term memory, and global cognition when compared to first generation antipsychotics, but have no benefit over first generation antipsychotics for improving attention, cognitive flexibility, working memory, delayed recall, or visuospatial processing. High quality evidence shows a small benefit of first-generation antipsychotics over placebo for general cognitive functioning.

For specific antipsychotics, moderate to high quality evidence shows haloperidol is associated with small improvements in global cognition (low haloperidol dose only), verbal learning (low and high dose), delayed recall (low and high dose), and attention (low dose only) when compared to second generation antipsychotics, with no differences in executive function, verbal fluency, motor skills, or processing speed. Sertindole may be superior to; clozapine, quetiapine, and first generation antipsychotics for general cognitive ability; clozapine, quetiapine, and olanzapine for memory; clozapine, quetiapine, olanzapine and ziprasidone for executive functioning; and quetiapine for processing speed. Olanzapine may be superior to clozapine and first generation antipsychotics for visuospatial skills and verbal fluency.

Moderate quality evidence finds small improvements in overall cognition after treatment with clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, particularly on measures of memory, attention, processing speed, and executive functioning. Fluency was improved with clozapine, olanzapine, and quetiapine only. There were no significant improvements in visuospatial skills, language, or motor functioning.

For other agents, moderate to high quality evidence suggests small benefits of antidepressants over placebo for global cognition and executive functioning. There was a small improvement in verbal learning with adjunctive anti-dementia medications compared to placebo, with no improvements in overall cognition, memory, speed of processing, attention, problem solving, executive functioning, social cognition or visual learning. There were no differences in adverse events between anti-dementia medications and placebo. There were no benefits of varenicline compared to placebo for cognition, and varenicline may cause more nausea.

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Constipation is a common side effect of antipsychotic medications, particularly clozapine, and occurs when bowel movements are infrequent and difficult to pass. Adjunct medications prescribed to treat side effects such as constipation may contribute to increasing adherence to antipsychotics which can reduce the risk of psychotic relapse.

What is the evidence for treatments for antipsychotic-induced constipation?

Moderate to low quality evidence suggests tuina massage or acupuncture are more effective than glycerol laxative suppository, and mannitol is more effective than rhubarb soda or phenolphthalein for relief of constipation caused by antipsychotics.

There were no other randomised controlled trials identified that assessed other forms of laxatives in people taking antipsychotics.

October 2020

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Depression is characterised by a depressed mood and/or a loss of interest or pleasure in activities. Symptoms of depression include changes in appetite, weight, sleep, and psychomotor activity, decreased energy, blunted affect, social withdrawal, difficulty concentrating or making decisions, feelings of worthlessness, hopelessness and guilt, and thoughts of suicide. As many symptoms are common to both depression and the negative syndrome of schizophrenia it can be difficult to identify a comorbid depressive illness in people with schizophrenia. Identifying and treating a comorbid depressive illness may increase the likelihood of recovery from psychosis and reduce the likelihood of psychotic relapse.

What is the evidence for medications for depression in people with schizophrenia?

For adjunctive antidepressants compared to placebo or no adjunctive treatment, moderate quality evidence finds a small effect of greater improvement in depressive symptoms with adjunctive antidepressants.

For antipsychotics alone compared to placebo, moderate to high quality evidence finds a large effect of greater improvement in depressive symptoms with sulpiride. There were medium-sized improvements with clozapine, amisulpride, and aripiprazole over placebo. There were small improvements with olanzapine, cariprazine, paliperidone, asenapine, quetiapine, risperidone, ziprasidone, lurasidone, haloperidol, and brexpiprazole. There were no improvements over placebo with clopenthixol, sertindole, flupentixol, chlorpromazine, perphenazine, zotepine, zuclopenthixol, thiotixene, loxapine, penfluridol, pimozide, perazine, trifluoperazine, molindone, or levomepromazine.

Moderate to low quality evidence suggests the antipsychotic clozapine may improve depression symptoms more than any other antipsychotic combined with the antidepressants amitryptiline, mianserin, meclobemide or placebo.

October 2020

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Dual diagnosis is the term used for people with both a mental illness like schizophrenia and substance use disorders. Studies targeting this population often investigate outcomes relating to both diagnoses, such as symptoms, substance use, social function, quality of life, and cognitive outcomes.

What is the evidence for medications for dual diagnosis?

Moderate to low quality evidence suggests olanzapine was superior to perphenazine, quetiapine, risperidone, and ziprasidone for overall symptoms in people with a dual diagnosis. Olanzapine was superior to perphenazine, quetiapine, and ziprasidone for positive symptoms, and olanzapine was superior to perphenazine, risperidone, and ziprasidone for negative symptoms.

The remaining evidence on antipsychotics and other agents (e.g. mazindol, lamotrigine, antidepressants, anti-craving agents, or disulfiram) for symptoms, substance use or other outcomes was based on small sample sizes, so no conclusions can be drawn.

October 2020

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Studies of the life course of schizophrenia suggest that positive symptoms tend to reduce with time, while negative symptoms, such as social withdrawal and emotional apathy, increase with time. In contrast, people with late-onset schizophrenia (onset after 40 years of age) and very late-onset schizophrenia (onset after 60 years of age) tend to have predominant positive symptoms and fewer negative symptoms.

This summary table includes both elderly people with chronic schizophrenia, and people who have been diagnosed with late-onset or very late-onset schizophrenia.

What is the evidence for medications for older people with  schizophrenia?

Moderate to high quality evidence finds a medium-sized benefit for overall symptoms, particularly negative symptoms, with olanzapine than with haloperidol in people with schizophrenia who are over 46 years of age There were no significant differences in symptoms for older patients between amisulpride and risperidone, chlorpromazine and clozapine, olanzapine and risperidone or quetiapine and risperidone.

There were fewer drop-outs with olanzapine than with risperidone, less prolactin increase with olanzapine than with haloperidol or risperidone, and less antiparkinson medication with olanzapine than with haloperidol. There were no differences in weight gain between these three agents.

October 2020

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People with a first episode of psychosis experience distressing symptoms such as unusual beliefs or abnormal behaviour (positive symptoms) and/or withdrawal or loss of interest in work or school (negative symptoms). Early intervention programs for schizophrenia and psychosis often combine many elements comprising both pharmaceutical and psychosocial therapies, and may involve enriched therapies that are tailored to an individual’s needs. The conclusions presented here are based on group data, and as such individual treatment programs need to be tailored by trained clinicians. Individual response to treatment can vary in terms of both symptoms and adverse effects.

What is the evidence on medications for first-episode psychosis?

For targeted early intervention services that include both antipsychotics and psychosocial components, moderate to high quality evidence finds small effects of greater improvements in symptoms, functioning, quality of life, and more remission and recovery than with treatment as usual.

Overall, there is a reasonable response to antipsychotics after a first-episode of psychosis; moderate quality evidence finds antipsychotics are associated with an 81% response rate when measured as a 20% reduction in symptoms, and a 52% response rate when measured as a 50% reduction in symptoms. For specific antipsychotics, high quality evidence finds greater improvement in overall symptoms with olanzapine than with haloperidol, and moderate to high quality evidence finds greater improvement in negative symptoms with olanzapine than with haloperidol, with no differences in positive symptoms. Moderate to high quality evidence finds greater improvement in overall symptoms with amisulpride or risperidone than with haloperidol. Moderate quality evidence finds greater improvement in overall symptoms with amisulpride than with quetiapine, and with ziprasidone than with haloperidol. There was greater improvement in negative symptoms with olanzapine than with risperidone, and greater improvement in positive symptoms with olanzapine than with quetiapine. There was greater improvement in both positive and negative symptoms with quetiapine than with haloperidol, and greater improvement in positive symptoms with risperidone than with quetiapine.

For relapse prevention, moderate to high quality evidence finds small effects of fewer relapses and hospitalisations with targetted early intervention services. Second-generation antipsychotics in general were found to be more effective than first-generation antipsychotics. Moderate quality evidence finds relapse and rehospitalisation rates were higher after discontinuation rather than maintenance of antipsychotics in people in remission following a first-episode of psychosis.

For treatment adherence, moderate to high quality evidence finds less all-cause discontinuation with targeted early intervention services. There was less all-cause discontinuation with risperidone than with haloperidol and less all-cause discontinuation with quetiapine than with haloperidol. Moderate to low quality evidence finds less all-cause discontinuation with aripiprazole or olanzapine than with haloperidol.

For side effects, olanzapine was associated with at least one use of drugs to treat parkinsonian symptoms. Quetiapine was associated with less akathisia than haloperidol, aripiprazole, risperidone, and olanzapine. Molindone resulted in less weight gain than risperidone, haloperidol, and olanzapine and less increase in prolactin release than risperidone.

October 2020

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