Friday, July 19, 2019

This review provides the following:

  • information about the marketing of antipsychotics for pediatric use
  • information about how antipsychotics act on the brain
  • a review of efficacy studies of antipsychotics for pediatric use
  • a review of short-term and long-term risks and harms

 

Abstract

Although the prescribing of atypical antipsychotics to children and adolescents took hold in the late 1990s and early 2000s, there is still a lack of good research on their short-term effectiveness. There is no evidence that the drugs provide a long-term benefit, for any condition. In a NIMH trial, the researchers concluded that “few” youth treated with antipsychotics benefit from the treatment at the end of one year. The drugs are known to cause a broad array of adverse effects, including metabolic dysfunction, diabetes, motor dysfunction, hormonal problems, poor global health and brain shrinkage. Withdrawal symptoms may be severe, and there is a risk that withdrawal can provoke psychotic and manic episodes.


Prescribing of Antipsychotics for Pediatric Use

The prescribing of antipsychotics for pediatric use is best understood through a commercial lens, as this practice arose in response to the marketing of the “atypical antipsychotics” that were approved by the FDA during the 1990s.

The first generation of antipsychotics—Thorazine, Haldol and so forth—were understood to be powerful drugs that caused a wide range of severe side effects. For that reason, they were rarely prescribed to children and adolescents. In 1987, fewer than 50,000 youth under age 18 in the United States were prescribed an antipsychotic.

The pharmaceutical companies and American psychiatry touted the new atypicals— Zyprexa, Risperdal and other “second-generation antipsychotics” (SGAs)—as “breakthrough” medications that were much more effective and safer than the first-generation antipsychotics (FGAs). Leading child psychiatrists, who were being paid by pharmaceutical companies to serve as their consultants, then provided both diagnostic and off-label reasons to prescribe these new agents to children and adolescents.

Up until this time, schizophrenia was thought to rarely occur in children and adolescents. However, academics in child psychiatry began arguing that some children previously seen as autistic or suffering from a developmental disorder actually had child onset schizophrenia, and thus could benefit from an atypical antipsychotic.

The reconceptualization of bipolar disorder was similar in kind.  Up until the “atypical” antipsychotics arrived on the market, bipolar disorder was understood to occur post puberty, with onset in the late teens or later. It was thought not to occur in prepubertal children. Then, in the mid 1990s, Joseph Biederman, a child psychiatrist at Massachusetts General Hospital, began arguing that “severe irritability” and “affective storms”—behaviors that in the past were seen as evidence of ADHD or conduct disorder—were in fact symptoms of “juvenile bipolar disorder.” Even preschool age children could suffer from this illness, and with this new diagnostic criteria in mind, the number of U.S. children diagnosed with bipolar disorder soared from 20,000 in 1994 to 800,000 in 2003.

The manufacturers now had an opportunity to get their atypicals approved for early-onset schizophrenia, juvenile bipolar disorder, and for treating “irritability” in autism, with five companies successfully making it through this regulatory hurdle.

(You can search for more information about individual psychiatric drugs here.)

At the same time, psychiatrists and family doctors regularly began prescribing the atypicals “off-label” for behavioral control purposes. The powerful drugs were seen as helpful for reducing aggressive behaviors and emotional outbursts, to help ADHD youth go to sleep (i.e. to counteract the effects of stimulant medication), or to make them less “impulsive.” Physicians also began prescribing them as adjunctive medications for anxiety and depression. A 2016 study found that two-thirds of pediatric prescriptions of antipsychotics were for off-label purposes.

All of this has led to a dramatic increased in the prescribing of antipsychotics to children and adolescents. Today, more than 1% of all youth under age 18 are prescribed an antipsychotic, or more than ten times the rate in 1987. These drugs are prescribed at particularly high rates to foster care children and poor youth covered by Medicaid insurance.

 

How Antipsychotics Act on the Brain

As parents seek to assess the merits of psychiatric medications for their children, and their possible risks and benefits, it is helpful to understand how these drugs “act” on the brain.

How brain neurons communicate

There are an estimated 100 billion neurons in the brain. Messages are passed along neuronal pathways in the brain via molecules, known as neurotransmitters, that act as “chemical messengers.”

The first (sending) neuron releases a neurotransmitter into the tiny gap between neurons, known as the synaptic cleft, and the neurotransmitter then binds with receptors on the second neuron. The neurotransmitter is said to fit into the receptor like a “key into a lock.”

This binding action either causes the second (receiving) neuron to fire or inhibits its firing. An excitatory response passes the message along the neuronal pathway; an inhibitory response dampens this neuronal activity. To end the message, the chemical messenger is then “transported” back into the first neuron and stored for later re-use.

Image: GSLC, University of Utah

The chemical imbalance hypothesis 

In the 1960s, researchers discovered how antipsychotics and antidepressants interfered with this messaging process, and their discoveries led to a hypothesis that mental disorders are due to chemical imbalances in the brain, which are then “fixed,” or put back to normal, by psychiatric drugs.

For example, antidepressants were found to increase levels of the neurotransmitter serotonin in the brain, and thus researchers hypothesized that depression was due to too little serotonin. Antipsychotics were found to block dopamine pathways in the brain, and so researchers hypothesized that schizophrenia was due to too much dopamine.

To test these hypotheses, researchers conducted studies to determine whether people with depression  had too little serotonin in their brain, or whether people with schizophrenia regularly had too much dopamine activity. Decades of research failed to provide the confirming evidence.

In 2005, Kenneth Kendler, coeditor in chief of Psychological Medicine summed up these research findings in this succinct way: “We have hunted for big simple neurochemical explanations for psychiatric disorders and have not found them.”

A paradigm for understanding psychotropic drugs

In a 1996 paper, then National Institute of Mental Health (NIMH) director Stephen Hyman provided a good description of how psychiatric medications actually “work.” The drugs are better understood as agents that create abnormalities in brain function.

Psychotropic drugs, Hyman noted, all perturb normal neurotransmitter activity in the brain. The brain, however, has various feedback mechanisms to monitor its neurotransmitter activity, and in response to the drug’s perturbation of its normal functioning, it goes through a series of “compensatory adaptations.” The brain is seeking to maintain its normal functioning.

For instance,  if a drug raises serotonin levels, the brain decreases its own serotonergic activity. If a drug blocks dopamine receptors, then the brain increases its dopaminergic activity. And so forth. At the end of this compensatory process, Hyman wrote, the brain is now functioning in a manner that is “qualitatively as well as quantitatively different from the normal state.”

Atypical antipsychotics block multiple neurotransmitters

The first-generation antipsychotics (FGAs) block dopamine receptors, and thus thwart the normal transmission of messages along dopaminergic pathways to three areas of the brain: the frontal lobes, the limbic system, and the basal ganglia. In response, the brain increases the density of its dopamine receptors. It is now said to be “supersensitive” to dopamine.

The second-generation antipsychotics (SGAs), which were marketed as “atypical antipsychotics,” are all broad-acting agents. In addition to blocking dopamine receptors, they may also bind with serotonergic, histaminergic, adrenergic, and muscarinic receptors. For the most part, the second-generation antipsychotics thwart the passage of messages along these various neuronal pathways, triggering an avalanche of compensatory adaptations in the brain. Because these drugs are so broad-acting, there is little understanding of all the compensatory changes they cause.

With this understanding in mind, parents can now ask: How does this blockade of neuronal pathways in the brain—and the unknown compensatory adaptations—affect a child or adolescent, both over the short term and longer periods of time?

 

Risks and Benefits of Antipsychotics for Pediatric Use

The prescribing antipsychotics to children and adolescents took hold on an “off label” basis, meaning there were no research findings to support this practice. Even today, more than two decades later, the research on pediatric use of antipsychotics consists of a mix of open-label studies, case reports, and short-term trials funded by pharmaceutical companies, all of which is seen to provide, at most, a “limited” evidence base for the short-term use of these drugs.

As the American Academy of Child and Adolescent Psychiatry concluded in a 2011 review, “There exists a paucity of methodologically rigorous studies evaluating the use of atypical antipsychotics in children and adolescents.”

Here are reviews of the efficacy of antipsychotics for treating adolescent schizophrenia, disruptive behaviors, and mania in pediatric bipolar patients.

Efficacy in treating adolescent schizophrenia

In 2013, the Cochrane Group, an international collaboration of researchers who conduct systematic reviews of the medical literature, published a report on the use of antipsychotics for treating adolescent schizophrenia (and related psychotic disorders). The Cochrane researchers identified 13 randomized trials, involving 1,112 patients ages 13 to 18, that met their criteria for review.

Only two of the 13 compared an SGA to placebo.  Both were six week studies. One was of olanzapine (Zyprexa) and the other of aripiprazole (Abilify). In addition to being funded by the makers of the drugs, the published reports were authored, in large part, by company employees. In both studies, the investigators could prescribe benzodiazepines and anti-cholinergic drugs to treat any emergent adverse symptoms.

In the olanzapine trial, the Cochrane investigators reported that there was no significant difference in the global state of the medicated and placebo cohorts at the end of the study, or any significant difference in response rates (which was  defined as a 50% drop in symptoms). Thirty-eight percent of the olanzapine patients responded, versus 26% of the placebo patients.

The Cochrane investigators reported that there was one positive outcome for the olanzapine group: 68% completed the six-week trial versus 43% of the placebo group. A higher completion rate is seen as a marker that the treatment may be more tolerable than placebo, and thus superior in that regard.

In the other study, “placebo” was compared to a 10 mg or 30 mg dose of aripiprazole. The Cochrane investigators reported that the “number of non-responders” was actually higher in the 10 mg aripiprazole group than in the placebo group, meaning that the drug was not efficacious at that dosage. There was no significant difference in completion rates between those randomized to aripiprazole or placebo.

The Cochrane investigators determined that the published data regarding quality of life and reduction of symptoms was “skewed,” and thus, in contrast to what the authors of the aripiprazole study claimed, they concluded there was no evidence of a drug benefit in those domains.

The other 11 studies compared drug vs. drug outcomes. The Cochrane investigators concluded that there was “no convincing evidence” that the SGAs were superior to the FGAs for the “treatment of adolescents with psychosis,” and that there was “very little evidence” that would support a claim that any SGA was better than another SGA.

In this collection of 13 studies, the researchers found “no data on hospitalization and service utilization outcomes, economic outcomes, behavior or cognitive response.”

Efficacy in treating disruptive behaviors

Given how antipsychotics “act” on the brain, these drugs could be expected to curb “disruptive behaviors.” An antipsychotic’s thwarting of normal dopamine pathways is known to reduce emotional responses and slow physical movements (which is why many patients treated with antipsychotics complain of feeling like “zombies”). For these reasons, antipsychotics  have long been used in zoos to make it easier to manage the more aggressive animals.

In a 2017 review, Cochrane researchers identified 10 randomized trials of SGAs for disruptive behaviors in children and adolescents that they found worthy of review. Nine of the 10 were funded by pharmaceutical companies, and only one lasted for more than 10 weeks. Five of the studies enrolled 25 or fewer patients.

Of the 10 studies, eight assessed the use of risperidone for such purposes. The researchers concluded that these studies collectively provided “some evidence” that this drug “led to a reduction of aggression, and conduct problems, to some extent, after six weeks of treatment.” At the same time, because of the many limitations of this research, the Cochrane researchers cautioned that it was “uncertain to what degree the efficacy found in clinical trials will translate into real-life clinical practice.”

The other two studies assessed the use of quetiapine (Seroquel) and ziprasidone (Geodon) for treating disruptive behaviors. The researchers concluded that there was a “lack of evidence” to support their use for this purpose.

The Cochrane report also noted that the 10 studies did not provide evidence that the use of SGAs, as a treatment for disruptive behaviors,” improved “general functioning, social functioning, school functioning, family functioning or parent satisfaction.”

Efficacy in treating mania

The Cochrane group has not published a systematic review of studies of the use of SGAs for treating mania in children and adolescents.

The FDA approved olanzapine, risperidone, quetiapine and aripiprazole  based on studies that lasted three to four weeks, with the researchers reporting, in each instance, that the SGA reduced mania significantly better than placebo. In the aripiprazole and olanzapine trials, between 45% to 64% of the medicated patients were reported to “respond” to the treatment, which was significantly higher than the response rates for the placebo groups.

Only the aripiprazole study followed the patients for a longer period of time. At the end of 30 weeks, 34% of the aripiprazole group remained in the study (66/197), compared to 12% of the placebo cohort (12/99.) The others dropped out due to loss of efficacy, adverse effects and other miscellaneous reasons.

This would indicate that roughly two-thirds of the medicated patients did not benefit, over the long term, from the drug treatment. Among those who did finish the study, there were no differences in manic symptoms between the aripiprazole and placebo cohorts.

Short-term efficacy and long-term outcomes in a government-funded study

In the one government-funded study of SGAs for pediatric use, dubbed the TEOSS study, 116 youth (8 to 19 years old) diagnosed with early onset schizophrenia were randomized to molindone (a FGA), risperidone, or olanzapine.

At the end of eight weeks, the response rate was 50% for those treated with molindone, 46% for those treated with Risperdal, and 34% treated with Zyprexa. Only 31 of the 76 youth treated with a SGA “responded” (meaning that 45 of the 76 were exposed to the hazards of an antipsychotic without gaining any significant reduction of their symptoms).

Those who responded during the first eight weeks (54 of 116) were then followed for an additional 44 weeks. During this time, 40 of the 54 youth dropped out of the study, mostly because of  “adverse effects” or “inadequate response.” Those treated with Risperdal worsened significantly in their functional capacities, while those treated with Zyprexa worsened slightly in this regard. (There was no change in the molindone group.) In addition, the psychotic symptoms of the children treated with Risperdal or Zyprexa worsened to a small extent during the followup.

Thus, in this government-funded study, which the NIMH touted as the first study designed to look at the longer-term effects of SGAs, only 14 of the 116 patients (12%) had responded to an antipsychotic and stayed on the drug and in the trial to its end. The remaining 102 (88%) either failed to respond to an antipsychotic or dropped out during the maintenance phase of the study.

In its press release, the NIMH drew the obvious bottom-line:  “Few youth with early onset schizophrenia who are treated with antipsychotic medications for up to a year appear to benefit from the initial treatment choice over the long-term.”

Adverse Effects

Although the SGAs are often grouped together as “atypical” antipsychotics, which suggests they share a common mechanism of action, these drugs act on a number of different neurotransmitter pathways and do so with varying degrees of potency. For that reason, the drugs have “adverse event profiles” that vary widely.

A drug’s disruption of a neurotransmitter pathway causes many predictable adverse events. Since dopaminergic pathways are involved in the control of motor movements, drugs that block dopamine receptors can cause Parkinsonian symptoms, muscle dystonias, and akathisia. In addition, dopaminergic pathways are vital to the normal functioning of the limbic system and the frontal lobes, and thus dopamine-blocking drugs may inhibit emotional responses to the world (a limbic system function) and self-awareness (frontal lobes.)  Blocking serotonergic receptors can cause an increase in appetite, weight gain, and metabolic changes associated with an increased risk of diabetes. Blocking muscarinic M1 receptors can cause memory and cognition problems. And so on. Each neurotransmitter has its own side effect profile.

As can be seen in the above graphic, SGAs may cause a dizzying array of physical, emotional and cognitive problems. The easiest way to conceptualize the risks of an individual SGA may be to look at the neurotransmitter pathways it blocks, and at what potency, and then see which adverse affects are associated with those pathways.

 

Researchers have also found that children and adolescents “are physically and emotionally more vulnerable to adverse effects.”

Metabolic Dysfunction

All SGAs may cause weight gain, with olanzapine (Zyprexa) the worst offender. In one six-month study of first-episode psychotic patients, the olanzapine-treated youth gained an average of 34 pounds. Israeli researchers reported that 90% of youth taking olanzapine and 43% of youth taking risperidone gained more  than 7% of their baseline weight within 12 weeks. When investigators at pediatric hospitals in Cincinnati and Vancouver surveyed their juvenile patients with exposure to SGAs, they found that more than 50% were overweight or obese. This weight gain may also cause pediatric patients to become depressed and suffer from low self-esteem.

The SGAs may also cause diabetes. In 2010, Canadian investigators reported that 22% of pediatric patients treated at a children’s hospital in British Columbia had “impaired fasting glucose and or type 2 diabetes.” Since fat tissue can increase insulin resistance and glucose intolerance, this diabetes risk may be secondary to the weight gain. However, it appears that SGAs may also directly impair pancreatic beta-cell function and promote insulin resistance in that way.

SGAs commonly cause a significant increase in trigylcerides and LDL-cholesterol (dyslipidemia). In a survey of 95 juvenile inpatients at Cincinnati’s Children Hospital who had been treated with an SGA for more than one month, 51% had developed dyslipidemia.

The weight gain, glucose intolerance, and dyslipidemia are all evidence that an SGA may profoundly impair the body’s metabolic system. If a pediatric patient becomes obese and develops two other signs of metabolic dysfunction (high blood pressure, dyslipidemia, or high fasting glucose), the child or adolescent is said to have developed a metabolic syndrome. A Canadian study found that 27% of juvenile patients suffered from this broader spectrum of metabolic dysfunction.

All of this, researchers have noted, may put the pediatric patients on a path toward poor long-term health and ultimately early death. “Because drug-induced metabolic changes can persist over time and may not be fully reversible upon drug discontinuation, the implications for distal health outcomes can be profound,” wrote the NIMH’s Benedetto Vitiello in 2009. “Age-inappropriate weight gain and obesity increase the risk for a variety of negative outcomes, such as diabetes, hyperlipidemia, and hypertension, which are major risk factors for cardiovascular diseases and reduced quality of life and life expectancy.”

Endocrine Dysfunction

SGAs may cause an increase in prolactin levels (and thus cause hyperolactinemia.) In 2007, Spanish investigators reported in 2007 that 49% of youth treated with an SGA for longer than a year had hyperolactinemia. This can cause breast enlargement and hypogonadism in males, and galactorrhea, amenorrhea, and hirsutism in females. Elevated prolactin levels may also cause a decrease in libido, sexual dysfunction and decreased bone density. Since this bone deficiency “may not be recovered later in life,” the SGA-treated child may end up with a lifelong risk of bone fractures.

Motor Dysfunction

First-generation antipsychotics were known to regularly cause motor problems (extrapyramidal symptoms, or EPS), and these problems show up in children and adolescents treated with SGAs too. In a double-blind, randomized study that directly compared EPS rates with an FGA and SGAs in youth under 18 years old, 67% of the haloperidol group experienced “substantial EPS,” versus 56% of those given olanzapine and 53% in the risperidone group.

In adults, longer-term use of antipsychotics may lead to tardive dyskinesia (TD), which is characterized by rhythmic, involuntary motor movements, such as a constant licking of the lips. Often, the abnormal movements don’t go away even if the antipsychotic is withdrawn, which is evidence that the basal ganglia have been permanently damaged. Although researchers have reported seeing almost no cases of TD in their short-term studies, two studies that looked at longer-term SGA use in children reported TD rates similar to what is seen in adult patients taking FGAs. Researchers at the University of Maryland reported that ten% of 116 pediatric patients they studied developed TD after they had been on SGAs for one to two years. Meanwhile, Spanish investigators found that 38% of children and adolescents on antipsychotics for longer than one year showed signs of mild TD.

Fortunately, it appears that TD is more likely to disappear in pediatric patients than in adults if the antipsychotic is withdrawn, and thus, in this age group, the appearance of TD symptoms may not mean that the damage to the basal ganglia is beyond repair.

Other Adverse Effects

The list of reported adverse events associated with SGA use seemingly touches every aspect of body and mind. The cardiovascular risks include cardiomegaly, tachycardia, arrhythmia, QT prolongation, heart disease not otherwise specified, and high blood pressure. In industry-funded trials, reported adverse events include dizziness, facial flushing, dry mucous membranes, increased sweating, constipation, urinary retention, headaches, blurred vision and tinnitus. Cases of neuroleptic malignant syndrome and pancreatitis, both of which can be fatal, have been reported in pediatric patients.

As for emotional and cognitive problems, in the NIMH’s TEOSS study, 26% of the patients reported feeling anxious. Five percent to twenty percent of pediatric patients may experience akathisia, an intense inner agitation (physical and mental) associated with an increased risk of suicide and violence. Other common side effects include irritability, depression, emotional lethargy and decreased concentration. SGAs are also sedating drugs, with more than half of the pediatric patients in some trials complaining of this effect, which is associated with “cognitive impairment and decreased mental activity.”

Poor Global Health

Given this range of adverse effects, surveys of children and adolescents that seek to identify adverse events regularly find that nearly all children treated with an SGA suffer an adverse event of some type. The TEOSS investigators reported that during the 44-week followup, 83% of the patients suffered an adverse event. A survey of 4,140 Medicaid youth treated with SGAs for longer periods of time found that 47% suffered from digestive or urogenital problems; 36% had skin, musculoskeletal or respiratory conditions; 9% had cardiovascular disorders; and 3% had diabetes. “The treated cohort exhibits a high incidence and diverse array of treatment-related adverse events,” the researchers concluded.

Possible Brain Shrinkage

MRI studies in adult patients treated with antipsychotics have found that use of FGAs and SGAs is “associated with smaller brain tissue volumes,” and that this shrinkage is dose related. This brain-shrinkage effect was also seen in macaque monkeys. German investigators concluded that this reduction in brain volume exerts a negative effect on “neurocognition, negative and positive symptoms (of schizophrenia), and psychosocial functioning.” While this adverse drug effect is not well studied in children and adolescents, Australian investigators warned in a 2018 paper that SGAs may cause “brain atrophy” in this age group as well.

Withdrawal Syndromes 

Much as researchers have identified the adverse effects associated with the blockade of specific neurotransmitters, they have done the same for withdrawal symptoms. As can be seen in the chart below, withdrawal from an SGA may be particularly problematic because they are broad-acting drugs that block multiple transmitters, leading to any number of possible withdrawal syndromes.

Summing Up the Evidence

As this review reveals, the “evidence base” for the prescribing of antipsychotics to children and adolescents is of a marginal sort. It comes from industry-sponsored trials, which don’t  include a true placebo group, and the trials—typically only three to six weeks long—focus primarily on the reduction of a target symptom as a primary outcome, as opposed to any “global” measures of health, cognition, and social functioning. There is no evidence that the drugs provide a long-term benefit, for any condition, and they may cause physical, emotional, and cognitive impairments.

Clinical Practice Guidelines

Given that antipsychotics are being prescribed to children and adolescents for a variety of reasons, there are significant differences in the the clinical practice guidelines that have been developed for their use. The National Institute of Clinical Excellence guideline developed in the UK is more conservative than the guidelines developed by U.S. professional organizations.

For a summary review of non-drug therapies for psychotic, bipolar and behavioral disorders in children, visit this page.

For more info:

Slide presentation. Medicating Children: When long-term outcomes are considered, is this an evidence based practice?

Video presentation: Psychotropic Drugs and Children

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