antipsychotic drugs

Two antipsychotic drugs prolong QTc interval, may cause arrhythmias, sudden cardiac death

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Key takeaways:

  • More than 13% of users of quetiapine and haloperidol developed severe QT prolongation.
  • Severe QT prolongation was linked to ventricular arrhythmia and, in quetiapine users, sudden cardiac death.

The antipsychotic drugs quetiapine and haloperidol were associated with severe QT prolongation, ventricular arrhythmias and sudden cardiac death, researchers reported in HeartRhythm.

“The use of the antipsychotics quetiapine and haloperidol to treat mental disorders is widespread,” Shang-Hung Chang, MD, PhD, of the cardiovascular division, department of internal medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan, said in a press release. “In an effort to enhance patient safety and optimize the management of individuals receiving these medications, we have investigated the incidences, risk factors and clinical outcomes of severe QT prolongation to provide valuable insights for health care professionals, patients and caregivers.”

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More than 13% of users of quetiapine and haloperidol developed severe QT prolongation.

Using electronic health records from a multicenter health care hospital system in Taiwan, the researchers analyzed data from 8,832 patients administered quetiapine (mean age, 69 years; 59% men) and 2,341 administered haloperidol (mean age, 66 years; 65% men). The outcomes of interest were incidence of severe QT prolongation, defined as a posttreatment corrected QT (QTc) interval exceeding 500 milliseconds or an increase in QTc interval of more than 60 milliseconds compared with baseline, risk factors for severe QT prolongation and clinical outcomes associated with severe QT prolongation.

Severe QT prolongation

The mean increase in QTc was 18.3 milliseconds in quetiapine users and 18.9 milliseconds in haloperidol users, with 13% of the quetiapine group and 14.2% of the haloperidol group developing severe QT prolongation, according to the researchers.

In both groups, risk factors for developing severe QT prolongation included age older than 65 years (P < .001 in quetiapine group; P = .033 in haloperidol group), hypokalemia (P < .001 in quetiapine group; P = .002 in haloperidol group), hypocalcemia (P < .001 in quetiapine group; P = .008 in haloperidol group) and hypomagnesemia (P = .004 in quetiapine group; P = .04 in haloperidol group), the researchers found.

In the quetiapine group, those who developed severe QT prolongation had greater incidence of ventricular arrhythmias (3.8% vs. 1.1%; P < .001) and sudden cardiac death (2.3% vs. 0.8%; P < .001) than those who did not, but there was no difference by severe QT prolongation status in syncope and seizure, Chang and colleagues wrote.

In the haloperidol group, those who developed severe QT prolongation had greater incidence of ventricular arrhythmias (3.3% vs. 1.6%; P = .039), but there was no difference by severe QT prolongation status in sudden cardiac death (P = .414), syncope and seizure, according to the researchers.

‘Be aware of the potential risks’

“Clinicians should be aware of the potential risks associated with quetiapine use, particularly the risk of severe QT prolongation and its associated outcomes, including ventricular arrhythmias and sudden cardiac death,” Chung-Li Wang, MD, of the cardiovascular division, department of internal medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan, said in the release.

In a related editorial, Clifford TeBay, BBSc (Hons), from the Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia, and Jamie I. Vandenberg, PhD, MBBS, FHRS, from the School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales in Sydney, wrote about a limitation of the study: “The age group studied was relatively old and likely included only small numbers of patients in their late teens/twenties, which is when schizophrenia is often first diagnosed and antipsychotic drug commenced. So, we cannot necessarily extrapolate the findings from the present study to this younger cohort that may have fewer comorbidities. Nevertheless, this study represents an important step forward into real-world monitoring of severe QT prolongation.”

“It would be prudent to undertake an ECG before and after commencement of an antipsychotic drug,” Vandenberg said in the release. “If it is an option, one could stop a drug causing QT prolongation and try a different antipsychotic. But if this is not practical, one should pay particular attention to reducing other risk factors, such as prescription of other drugs that may exacerbate QT prolongation, and be vigilant for hypokalemia.”

Type 2 diabetes: Could old antipsychotic drugs be an alternative to metformin?

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Some existing medications could be used to treat type 2 diabetes. Philippe Clement/Arterra/Universal Images Group via Getty Images

  • A new study finds that an older class of antipsychotic medications can lower blood sugar in people with type 2 diabetes.
  • These drugs may address the needs of people who cannot take existing diabetes medications, or for whom they have become less effective.
  • The antipsychotics address the expression of an enzyme that has recently been tied to hyperglycemia in mice.

With type 2 diabetes (T2D) on the riseTrusted Source, there is an expanding need for effective treatments. Researchers from the University of Alberta (UAlberta) in Canada have been exploring existing non-diabetes drugs as new therapeutic options for people with T2D.

The study has found that a class of older antipsychotic drugs reduces blood sugar levels by targeting an enzyme tied to hyperglycemia in diabetes.

The enzyme the drugs inhibit is succinyl CoA:3-ketoacid CoA transferase or SCOT. The drugs belong to the diphenylbutylpiperidines medication class, abbreviated as DPBP.

The study is published in the journal Diabetes.

When metformin is not an option

Many people with T2D cannot benefit from metformin — the primary drug prescribed for lowering blood sugar — or other existing diabetes medications.

About one-third of patientsTrusted Source with T2D cannot benefit from metformin due to variable drug responses associated with genetic and non-genetic factors

Its corresponding author John R. Ussher, associate professor at the Faculty of Pharmacy and Pharmaceutical Sciences, explained to Medical News Today that new therapies are also needed for people with late-stage T2D:

“They become less responsive to the multiple medications that improve their blood sugar control by increasing insulin secretion.”

“Type 2 diabetes is very prevalent in our society, with enormous costs on the population from a health standpoint, and financially for our health system overall,” said Dr. Jason Ng, endocrinologist at the UPMC Endocrinology & Diabetes Center in Pittsburgh, PA. (Dr. Ng was not involved in the study.)

“Developing novel therapies to help improve sugar control in type 2 diabetic patients is a key method in improving outcomes both in the micro and macroenvironment,” alongside lifestyle and dietary changes, said Dr. Ng.

How re-purposing existing drugs helps

Developing a new drug takes a long time — The PhRMA Foundation estimates it takes an average of 10 years. It is also an expensive process. Reimagining uses for an already existing drug is a far speedier, simpler process.

When re-purposing approved drugs for new uses, much of this work has already been done.

Basic safety concerns have already been satisfied, so clinical trials, which are still necessary, can take place more quickly.

Similarly, much of the time and money that goes into development has already been spent, simplifying the process considerably.

Anti-psychotics and blood sugar levels

In 2020, the UAlberta researchers published a studyTrusted Source documenting the link between SCOT and hyperglycemia in mice.

They also demonstrated that a DPBP drug, pimozide, could lower the expression of SCOT, and that this resulted in an improvement in blood sugar levels.

That study had identified DPBP drugs through computer modeling. The new research finds that the entire class of drugs can inhibit SCOT expression.

In addition to a drug’s primary action, many also produce secondary effects, such as the DPBP drugs’ ability to inhibit SCOT.

This connection opens up new therapeutic options since diabetes drugs typically decrease blood sugar through an increase in insulin levels.

“[DPBP drugs’ ability to lower SCOTs expression is] a potential new mechanism in which we can promote a sugar lowering effect in patients with type 2 diabetes and obesity, which is promising but needs further study.”
— Dr. Jason Ng

At healthy levels, SCOT helps the body burn ketones as an alternate fuel when glucose is in short supply. Inhibiting SCOT expression prevents the use of this backup energy source, a concern expressed in the study.

According to Dr. Ussher, ”the consequence is indeed an increase in blood ketone levels, which may increase the risk of ketoacidosis as a side effect.”

He noted, however, that his team’s pre-clinical studies in animals suggest that this is likely to be no more severe than ketoacidosis that occurs with a ketogenic diet. He said that it will be important to monitor ketone levels for those taking DPBP medications.

“It is imperative that we understand what the long-term consequences may be for inhibiting SCOT in humans,” he stressed.

Side effects of DPBP drugs for diabetes

As antipsychotic medications, the DPBP class of drugs target dopamine receptors in the brain. As such, their often-reported side effects include drowsiness, dizziness, and fatigue.

“We are interested in determining whether we can modify the structure of the DPBPs so that they are unable to penetrate the brain but preserve their ability to inhibit SCOT everywhere else in the body,” said Dr. Ussher.

Doing so would not only eliminate the side effects but also allow the brain to continue utilizing ketones for energy as needed.

“We have actually made some progress in this area and hope to publish our follow-up studies in this direction in the next year or two,” Dr. Ussher added.

Diet and lifestyle tips for controlling T2D

For now, the best advice for people hoping to avoid T2D or to get the disease under control, according to Dr. Ng, is “Eating a healthy diet that is not carb-heavy, getting plenty of physical activity, getting plenty of sleep, and reducing stress.”

“These are all common ways to feel healthier, and they all also help your body maintain good insulin sensitivity, reduce the risk of developing obesity, and in turn, reduce the risk of developing type 2 diabetes.”

Antipsychotic drugs linked to slight decrease in brain volume

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    A study published today has confirmed a link between antipsychotic medication and a slight, but measureable, decrease in brain volume in patients with schizophrenia. For the first time, researchers have been able to examine whether this decrease is harmful for patients’ cognitive function and symptoms, and noted that over a nine year follow-up, this decrease did not appear to have any effect.

As we age, our brains naturally lose some of their volume – in other words, and connections. This process, known as , typically begins in our thirties and continues into old age. Researchers have known for some time that patients with schizophrenia lose at a faster rate than healthy individuals, though the reason why is unclear.

Now, in a study published in the open access journal PLOS ONE, a team of researchers from the University of Oulu, Finland, and the University of Cambridge has identified the rate of decrease in both healthy individuals and patients with schizophrenia. They also documented where in the brain schizophrenia patients have more atrophy, and have examined links between atrophy and antipsychotic medication.

By comparing of 33 patients with schizophrenia with 71 over a period of 9 years – from age 34 to 43 – the researchers were able to show that schizophrenia patients lost brain volume at a rate of 0.7% each year. The control participants lost brain volume at a rate of 0.5% per year.

Scientists have previously speculated that antipsychotic medication used to treat schizophrenia may be linked to this decrease in brain volume. Today’s research confirms this association, showing that the rate of decrease in volume was greater when the dose of medication was higher. However, the mechanisms behind this – and whether it was in fact the medication that was causing this greater loss of tissue – are not clear. Some researchers have previously argued that whilst older might cause brain volume decreases, newer antipsychotic medications may protect against these decreases. However, today’s research suggests that both classes of antipsychotic medication are associated with similar declines in brain volume.

The researchers also looked at whether there was any link between the volume of brain lost and the severity of symptoms or loss of cognitive function, but found no effect.

Professor Juha Veijola from the Department of Psychiatry at the University of Oulu, Finland says: “We all lose some brain tissue as we get older, but people with schizophrenia lose it at a faster rate. We’ve shown that this loss seems to be linked to the antipsychotic medication people are taking. Research like this where patients are studied for many years can help to develop guidelines about when clinicians can reduce the dosage of antipsychotic medication in the long term treatment of people with .”

“It’s important to stress that the loss of brain volume doesn’t appear to have any effect on people over the nine year follow-up we conducted, and patients should not stop their medication on the basis of this research, ” adds Dr Graham Murray from the Behavioural and Clinical Neuroscience Institute and the Department of Psychiatry at University of Cambridge. “A key question in future will be to examine whether there is any effect of this loss of brain volume later in life. We need more research in larger studies with longer follow-ups to evaluate the significance of these brain changes.”

Maintenance treatment with antipsychotic drugs for schizophrenia.

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This Cochrane Review of the use of antipsychotic drugs as maintenance treatment for patients with schizophrenia builds on work that was started nearly four decades ago by one of its authors, John Davis from the University of Illinois in Chicago, USA. At that time, the evidence base showed that continuing with antipsychotic treatment reduced relapse rates but many questions remained. Some of these questions have been answered by subsequent randomised trials and this new Cochrane Review brings the evidence together, to provide information on different types and duration of drug, different types of patients and outcomes additional to relapse.

The review includes 65 randomised trials, with nearly 6500 participants, and uses risk ratios and numbers needed to treat to benefit and to harm to quantify the findings where meta-analyses were possible. The trials span six decades of research, and were published between 1959 and 2011. They also contain considerable heterogeneity in factors such as the antipsychotic drug used, definitions of relapse, study duration, setting, and speed of withdrawal of the antipsychotic in the placebo group. This anticipated heterogeneity led the authors to choose a random-effects meta-analysis as their principle analysis, but they also used the fixed-effect model in a sensitivity analysis for the primary outcome, which was relapse at seven to twelve months after randomization.

The main analysis found that antipsychotic drugs reduced the risk of relapse by nearly two thirds. In 24 randomised trials, with close to 2700 patients, the proportion of patients who relapsed if they were randomised to antipsychotic drugs was 27%, compared to 64% in the placebo group. This absolute reduction in risk corresponds to a number needed to treat to benefit of 3. In the sensitivity analysis, using the fixed effect model for the meta-analysis, the result was very similar, with the same risk ratio 0.40 as in the random-effects meta-analysis but a narrower 95% confidence interval of 0.36 to 0.44, rather than 0.33 to 0.49.

Antipsychotic drugs reduced the need for rehospitalisation and the risk of aggressive behaviour. This latter finding is important because, although aggressive acts of people with schizophrenia are rare, they can have dire consequences for the patients and those around them, as well as contributing detrimentally to the stigma about the disorder. In the three trials (527 patients) that were combined in the review’s analysis of quality of life, this was found to be better in the antipsychotic group. However, the drugs do have side effects, with weight gain, sedation and movement disorders being more common among patients allocated to antipsychotic drugs than those in the placebo group. One of the side effects of interest, mortality, could not be investigated because of a lack of data in the trials. This analysis would have been particularly important because it is possible that antipsychotics might increase mortality due to side effects or might decrease it by, for example, preventing suicides.

The size of this review also allowed the authors to perform a series of pre-specified subgroup analyses. These showed that first-episode patients, patients who had been in remission when randomised, and patients who had been stable for various periods of up to 3-6 years when randomised experienced fewer relapses in the antipsychotic drug group than in the placebo group. This suggests that patients who have been stabilised for 3-6 years cannot be considered to have been cured and that stopping their medication might do more than harm than good. Furthermore, the review does not support the hypothesis that any superiority of antipsychotic drugs over placebo is due to supersensitivity psychosis which would arise after abrupt discontinuation of antipsychotics, because the comparison of abrupt versus gradual withdrawal did not show an important difference in the risk ratio for relapse.

The authors of the review also performed a meta-regression to match the size of the effect on relapse with the duration of the study. This found that the drug-placebo difference got smaller the longer the studies lasted, which is counterintuitive since it implies that the best effects come from stopping the drugs sooner rather than later, but that stopping the drugs is worse than not stopping them. This might mean that antipsychotics lose their efficacy over time, but it could also arise because of confounders in the trials which can impact on any meta-regression. In these trials, for example, decreasing compliance over time could be an alternative explanation for the finding.

Although this Cochrane Review shows that many of the questions that remained unanswered after the 1975 overview have now been answered, important uncertainties remain which require further research. The authors suggest that this research should study patients for longer than two years and that studies in general should make greater efforts to measure outcomes other than relapse, including those related to rehospitalisation, social participation, compliance and death. They include the design of a suitable trial within their implications for research to stimulate those who might undertake such research.

Source: Cochrane Library