More Harm Than Good?
WEIGHING IN ON THE BENEFITS & ADVERSE EFFECTS OF ANTIPSYCHOTICS.
Antipsychotic medications (antipsychotics) are widely prescribed for a variety of illnesses and disorders to people of all ages. They were initially used primarily to help people with schizophrenia and related psychoses.
But their use has expanded dramatically, and they are now prescribed for a range of other conditions, including severe depression, bipolar disorder, anxiety, obsessive-compulsive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, Tourette syndrome, insomnia, autism, and dementia.
According to a fact sheet published by IQVIA, more than 1.5 million individuals in Canada used antipsychotic medications in 2022, an increase of 19% since 2019.
That equates to a prevalence rate of 4% in 2022 for the Canadian population overall. The prevalence is 23% higher among women than men.
Statistics for antipsychotic use in the United States indicate that the prevalence overall was 1.6%, based on pooled data from 2013-2018. Just as in Canada, usage of antipsychotics in the U.S. is higher among women than men – with 53.3% of usage by women vs. 46.7% by men.
The effectiveness of antipsychotics is well-established, especially for reducing and controlling such psychosis symptoms as hallucinations, delusions, and disordered thinking. However, antipsychotics also have wide-ranging adverse effects that vary depending on the type being used. This article reviews some of the latest findings about these adverse effects.
A HISTORY OF HELP & HARM
First-generation antipsychotics – discovered in the 1950s – revolutionized psychiatric care for people with severe mental illness, allowing many of them to be discharged from hospitals and be treated in the community instead.
Since antipsychotics do not “cure” psychosis but instead only treat the symptoms, people usually took them indefinitely.
However, taking these first-generation antipsychotics for this length of time commonly resulted in many troubling side effects, including muscle stiffness, tremors, tics, and tardive dyskinesia (a movement disorder involving involuntary facial tics such as lip-smacking, sticking out the tongue, grimacing and/or frequent blinking).
So, people enthusiastically welcomed the second generation of antipsychotics, which were introduced in the 1990s and promised all the benefits of the first-generation medications without the negative movement-related side effects.
Fairly quickly, though, it became clear that these new medications, while avoiding movement problems, were commonly causing adverse metabolic effects such as severe weight gain and Type 2 diabetes that, in the long term, were negatively impacting health and shortening lifespan.
Over the years, research has linked antipsychotics to a wide range of additional adverse effects beyond the most common movement-related and metabolic effects, including cognitive impairment, brain shrinkage, seizures, coronary heart disease and stroke, acute respiratory failure, sleep apnea, embolism, dry mouth, drooling and cavities, osteoporosis, and impulse control disorders. Although the list of potential side effects is quite long, not all of these effects are common or supported by robust research evidence.
A recent academic review by Dr. Seena Fazel and colleagues – published in Neuroscience and Biobehavioral Reviews in 2023 – looked at the current state of research on the adverse effects of both generations of antipsychotics. After synthesizing the evidence from 32 meta-analyses involving almost 40 million participants, the researchers found that 47 adverse effects had been reported.
Of those, 32 adverse effects were rated moderate or high for consistency and robustness of the findings. Among those 32 adverse effects, the ones with the highest effect size were metabolic syndrome, urinary incontinence, sudden death, blurred vision, hypertonia, somnolence, and gait abnormalities.
According to Dr. Fazel, a professor of forensic psychiatry at the University of Oxford in England, among all the adverse effects reported in the research they reviewed, three types had the most consistent evidence:
1. endocrine and metabolic effects;
2. movement-related outcomes; and
3. sedation and sleep-related outcomes.
“It’s clear that both the first- and second-generation antipsychotic medications come with a host of possible adverse effects, some of which are common and a small proportion of which could be serious,” he said.
“The benefits these medications provide have to be weighed against these potential adverse effects when deciding who should take which of these medications, at what dose, and for how long.”
Dr. Fazel felt more research using different research designs is needed to help update and refine best practices for prescribing antipsychotics. This is complex because there is a gradient of effectiveness for different antipsychotic medications, with each kind coming with a different balance of benefits and risks.
“Although our review focused on outlining potential negative side effects and found evidence of such in trials and observational studies, it’s important to remember that there is a strong and robust evidence base for their efficacy for many outcomes in severe mental illness, including symptomatic improvement to reduce relapse and readmission rates,” he noted.
“Also, the quality of much of the research on adverse effects that we reviewed was low, so more research on longer-term outcomes of using antipsychotics is necessary.”
ANTIPSYCHOTICS FOR PEOPLE WITH DEMENTIA
Antipsychotic medications are frequently prescribed for people with dementia to help manage some of the more challenging behavioural and psychological symptoms of dementia, e.g., agitation, aggression, irritability, delirium, and psychosis.
A 2017 review by Dr. Julia Kirkham and colleagues, published in The Canadian Journal of Psychiatry, reported that ‘approximately one-third of all persons with dementia are currently prescribed antipsychotic medications.’ This is despite safety warnings by regulatory agencies in many countries.
For example, the U.S. Food and Drug Administration issued a “ black box” warning in 2005 for the use of all second-generation antipsychotics for people with dementia due to increased mortality risk. In 2008, they extended the warning to all first-generation antipsychotics as well.
Increased mortality is not the only adverse effect of antipsychotics for people with dementia, though. A recent study that involved more than 170,000 people with dementia – by Dr. Pearl Mok and colleagues, published in 2024 in The BMJ – found that the use of antipsychotics in dementia was linked to a wider range of serious harms than previously acknowledged in regulatory safety warnings.
Specifically, that study found that current use of any antipsychotic was associated with an increased risk of pneumonia, acute kidney injury, blood clots, stroke, heart attack, fracture, and heart failure.
“In the 90 days after a prescription, the risk was highest for pneumonia, acute kidney injury, stroke, and blood clot, with the increased risk ranging from 1.6-fold for blood clot to two-fold for pneumonia, compared with non-use,” said Dr. Mok, a research fellow at the University of Manchester in England.
“In addition, not only did we discover a wider range of harms associated with antipsychotic use by people with dementia, we found that the risks were highest in the first seven days after initiation of antipsychotic treatment, with the risk ranging from 2-fold for blood clot to ten-fold for pneumonia, compared with non-use, during this period. These findings underscore the need for even more caution in the early stages of using these types of drugs with this population.”
Dr. Mok’s study adds further support for existing policies and position statements worldwide calling for the reduction in antipsychotic use for those with dementia, including the “American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.”
According to the 2023 version of those criteria, antipsychotics should only be used by people with dementia if “documented nonpharmacologic options (e.g., behavioral interventions) have failed and/or the patient is threatening substantial harm to self or others.”
Further, it recommends that if antipsychotics are used, periodic deprescribing should be attempted to assess ongoing need and aim for the lowest effective dose.
So, it turns out that the answer to the question of whether antipsychotics do more harm than good is … it depends.
Although these medications can have many unwanted side effects, they can be extremely valuable for some people. Because there are many types of antipsychotic drugs available and the effects of these medications (both positive and negative) vary from person to person, many variables must be considered by a doctor when making an antipsychotic prescription decision.
For the people who are prescribed an antipsychotic, it might involve some experimentation over time to find the best medication and the right balance where the dose and duration of treatment provide optimal benefits while minimizing the adverse effects.
SEX DIFFERENCES WITH ANTIPSYCHOTICS
There are sex differences in the prevalence of antipsychotic use, with women more likely to take these medications than men. That’s not the only sex difference when it comes to antipsychotics, though.
A 2024 review by Dr. Mete Ercis and colleagues – published in Journal of Affective Disorders – found that there are also potential differences in the effectiveness and adverse effects of antipsychotics. They concluded that “women may respond better to antipsychotics than men, but also experience more side effects.”_____________________________________________________________
TYPES OF ANTIPSYCHOTICS & HOW THEY WORK
Antipsychotic medications, also known as neuroleptics, help reduce psychosis symptoms by altering brain chemistry.
First-generation (or typical) antipsychotics reduce the amount of the brain chemical dopamine by blocking dopamine receptors. Examples include chlorpromazine, flupenthixol, afluphenazine, haloperidol, loxapine, perphenazine, pimozide, trifluoperazine, thiothixene, and zuclopenthixol.
Second-generation (or atypical) antipsychotics block dopamine, too, while also affecting serotonin levels. Examples include risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazone, and clozapine.
The newer, i.e., second-generation, antipsychotics are more widely used, although some people still use the first-generation medications.
A black box warning is the most serious type of warning placed on medication, used when there is reasonable evidence of a serious hazard.
Source: Mind Over Matter V19