Monday, February 18, 2019

This review provides the following:

  • information about the diagnosis of depression in children and adolescents
  • information about how antidepressants act on the brain
  • a review of the safety and efficacy of antidepressants in children and adolescents
  • a review of clinical care guidelines for treating adolescent depression


Diagnosis of Depression in Children and Adolescents

Until the arrival of Prozac on the market in 1988, few children and adolescents were diagnosed with depression. The understanding before that time, as Harvard Medical School psychiatrist Ronald Kessler later wrote, was that “mood disorders are rare before adulthood and that mood disturbance is a normative and self-limiting aspect of child and adolescent development.”

However, once Prozac and other SSRIs came to market, academic psychiatrists rethought this belief. They began arguing that adolescent depression had long gone “underrecognized” and “undertreated,” and then, with funding from pharmaceutical companies, they reported that clinical trials had shown that SSRIs were an effective treatment in this age group. By the late 1990s, the reconceptualization of moodiness in children and adolescents as an illness, as opposed to a normative part of childhood, was complete.

“Until about 15 years ago, no one thought children could suffer depression,” the New York Times reported in 1997.  “Now experts estimate it afflicts about four million American children, or five percent.”

In its DSM IV and DSM 5 diagnostic manuals, the American Psychiatric Association set criteria for diagnosing pediatric depression that expanded on the symptom list used to diagnose major depression in adults. Most notably, irritation was identified as a core sign of childhood depression. DSM-5 states that if a child is depressed or irritable, then four of the following eight symptoms must be present during a two-week period to make the diagnosis:

  • Decreased interest or lack of enjoyment
  • Decreased concentration or indecision
  • Insomnia or hypersomnia
  • Change of appetite or change of weight
  • Excessive fatigue
  • Feelings of worthlessness or excessive guilt
  • Recurrent thoughts of death or suicidal ideation
  • Psychomotor agitation or retardation

In addition, for a diagnosis of major depressive disorder to be made, the presence of such “symptoms” must be seen as causing “significant functional impairments in school, social settings, and/or family.”

Based on these diagnostic criteria, one in nine adolescents is now said to suffer a major depressive episode each year. The annual prevalence rate is three times higher for adolescent girls (17.3%), than it is for adolescent boys (5.7%).

Source: R. Mojtabi. “National trends in the prevalence and treatment of depression in adults and young adults.” Pediatrics 138 (2016):e2016878

 

The DSM also lists  depressive disorders of a milder sort, and if a moody child doesn’t “meet the criteria for any of the other depressive disorder categories,” a diagnosis of “unspecified depressive disorder” can be made. Antidepressants may be prescribed for these milder conditions, and are also prescribed for pediatric anxiety disorders.

The prescribing of antidepressants to children and adolescents steadily climbs as they age, and by age 17, about one in every 15 youth is prescribed an antidepressant. That was the data in 2014, and that rate is thought to have increased since then.

 

How Antidepressants 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 neuron releases a neurotransmitter into the tiny gap between neurons, which is known as the synaptic cleft, and the neurotransmitter 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 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 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 in the brain.

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 both “qualitatively as well as quantitatively different from the normal state.”

Antidepressants alter serotonin function

Selective serotonin reuptake inhibitors (SSRIs) work by blocking the normal reuptake of serotonin from the synaptic cleft, and thus this neurotransmitter stays longer in that gap than normal. As such, it is thought to increase serotonergic activity.

Serotonin is a very common neurotransmitter. In response to this “perturbation,” the brain decreases its own serotonergic activity. Brain neurons begin to release less serotonin and, within a short period of time, the “entire pool of serotonin in the forebrain declines. In addition, neurons decrease the density of their brain receptors for serotonin. Chronic treatment with an SSRI may lead to a 50% reduction in serotonin receptors in the brain. At that point, the brain has become “densensitized” to serotonin.

SNRI antidepressants block the normal reuptake of both serotonin and norephinephrine, and as such, the expectation would be that the brain, because of its compensatory mechanisms, would become desensitized to both of these neurotransmitters.

With this understanding in mind, parents can now ask: how do these changes in brain function affect a child or adolescent, both over the short term and longer periods of time? What does the evidence show?


Risks and Benefits of Antidepressants for Pediatric Use

Short-term efficacy

Unfortunately, the published results of industry-funded trials of antidepressants for pediatric use are known to be unreliable. Negative findings were spun into positive results; suicidal events in the treated group were hidden; adverse effects were downplayed or went unreported. This type of corruption was also present in a large study of pediatric depression by the NIMH. “The story of research into selective inhibitor use in childhood depression is one of confusion, manipulation, and institutional failure,” the Lancet wrote in a 2004 editorial.

Even so, a 2016 meta-analysis of the published literature, which assesses the outcomes from 34 trials involving 5260 patients and 14 antidepressants, found little evidence that these drugs provide any benefit over placebo in children and adolescents. The “quality of the evidence was very low,” the investigators wrote, with 88% of the studies rated at high or moderate risk of bias. In this review of low-quality, biased trials, the only antidepressant that was found to provide a “statistically significant benefit” in depressed youth was fluoxetine (Prozac).

In 2018, investigators who relied on FDA reviews of such trials, or found some other method for accessing trial data (and thus did not rely on reports published in the medical journal), found that all 20 pediatric studies of antidepressants conducted from 1990 to 2005 were negative on primary outcome measures (such as reduction of depressive symptoms). The drugs provided no benefit over placebo. This was true of the two trials of fluoxetine that, in the published reports, told of a drug that provided a “statistically significant benefit” in children and adolescents. Most of the 15 studies conducted since 2005 were also negative on their primary outcome measures.

In their 2018 review, the investigators did find some evidence that SSRIs might provide a benefit for treating pediatric OCD and anxiety disorders. The emotional numbing that is often a side effect of such drug treatment may provide a benefit in these conditions.

In spite of the negative findings from these two meta-analyses, the FDA has approved fluoxetine and escitalopram for pediatric depression. It also has approved duloxetine for generalized anxiety disorder in pediatric patients; and fluoxetine, fluvoxamine, and sertraline for pediatric OCD.

The FDA has also approved one older antidepressant, the tricyclic clomipramine (Afranil), to treat depression in youth 10 to 18 years old. However, the efficacy data for this older class of drugs is even more suspect than it is for the SSRIs and SNRIs. As a 1992 editorial in the Journal of Child and Adolescent Psychopharmacology acknowledged, “research studies certainly have not supported the efficacy of tricyclic antidepressants in treated depressed adolescents.” The prescribing of antidepressants to children and adolescents, on any sort of frequent basis, began with the arrival of the SSRIs and SNRIs in the 1990s,  and thus this MIA review is focused on those two classes of drugs.

Risks

In addition to being a very common neurotransmitter, serotonin plays a vital role in gut function and is found in the blood plasma too. As a result, SSRIs and SNRIs can cause a wide range of physical, emotional, and psychiatric adverse effects in both adults and children.

Side effects 

SSRIs and SNRIs may cause nausea, vomiting, insomnia, sedation, constipation, fainting, sweating, headaches, palpitations, rashes, weight gain,  blurred vision, tremors, shivering, high fever and seizures. Emotional and psychiatric side effects include depersonalization, derealization, confusion, mania and psychosis.  In teenagers and adults, sexual dysfunction is common, and a significant percentage of youth may experience a severe inner agitation called akathisia, which is associated with an increased risk of violence and suicide.

Studies of children and adolescents followed for longer periods of time reported that such side effects—and particularly adverse emotional and psychiatric effects—are quite common. In a study of 82 children treated with an SSRI at Massachusetts General Hospital in Boston, 10% became psychotic and another 6% became manic. “One of the most disturbing adverse outcomes is a worsening of emotional, cognitive, or behavioral symptoms,” they wrote. A North Carolina psychiatrist reported that 28% of 128 children and adolescents he treated with SSRIs developed some type of “behavioral toxicity.”

Suicide

In the short-term clinical trials of SSRIs, 4% of the medicated youth became “suicidal,” which was double the rate for those on placebo. This led the FDA to put a black box warning on antidepressants that they increased the risk of a suicidal event.

In a large NIMH study, known as the TADs study, 22% of adolescents treated with an SSRI had a suicide event, compared with 6.7% of those not taking the drug. Seventeen of the 18 youth who attempted suicide during the study were taking an antidepressant.

Source: B. Vitiello.”Suicidal events in the treatment for adolescents with depression.” J. Clin Psychiatry 70 (2009):741-7.

 

Meanwhile, a 2006 study of two cohorts of youth 6 to 18 years old, with matched severity of depression, found that the group treated with an antidepressant were significantly more likely to attempt and complete suicide.

From 2005 to 2012, antidepressant use among youth rose 26%. During this same period, the suicide rate for youth 10 to 19 years old increased from 4.4 per 100,000 youth to 5.0 per 100,000, a rise that might be expected, given the research showing that exposure to an antidepressant increases the likelihood that children and adolescents will “attempt and complete suicide.”

Conversion to Bipolar Disorder

It has long been known that antidepressants increase the risk that a person diagnosed with unipolar depression will suffer a manic episode and be newly diagnosed with bipolar disorder. In 2004, Yale University investigators determined that risk was particularly pronounced for children and adolescents. The use of an antidepressant increased the conversion risk seven-fold for children 5 to 9 years old, four-fold for those 10 to 14 years old, and slightly more than two-fold for those 15 to 19 years old.

Source: A. Martin. “Age effects on antidepressant-induced manic conversion,” Arch of Pediatrics & Adolescent Medicine(2002) 158: 773-80.

 

Those increased risks occurred during the first ten months of treatment. At the end of four years, researchers reported that 25% of depressed children treated with an antidepressant have converted to a bipolar diagnosis. At the end of 10 years, 50% of youth diagnosed with depression before they hit puberty had converted to bipolar disorder, researchers at Washington University found.

With the prescribing of SSRIs to children and adolescents taking off in the 1990s, so too did the number of youth diagnosed with bipolar disorder. The percentage of children 0 to 19 years old so diagnosed rose forty-fold from 1994 to 2003.

Tardive Dysphoria 

There are a number of long-term studies in adults that have found that antidepressant treatment increases the likelihood that a person will become chronically depressed. This has led researchers to hypothesize that antidepressants induce compensatory changes in the brain—e.g. the depletion of serotonin in the forebrain and the decrease in serotonin receptors—that make people more biologically vulnerable to depression than they otherwise would have been. This, said one researcher, “may cause a worsening of the illness, continue for a period of time after discontinuation of the medication, and may not be reversible.”

This dysphoria may be different in kind from depression: Those suffering from it complain of feeling numb, or simply not caring about others. It appears that it not be so much a depressive state, but rather “I just don’t care about anything” state. While this long-term worsening hasn’t been studied in youth, it is thought to be due to the desensitization of the serotonergic system, which is a regular occurrence with exposure to an SSRI or SNRI.

In an international survey of nearly 1,500 adult users of antidepressants from 38 countries, roughly two-thirds complained of dysphoric effects.

J. Read. “Adverse effects of antidepressants reported by a large international cohort: emotional blunting, suicidality, and withdrawal effects.” Current Drug Safety 13 (2018):176-186

Withdrawal Symptoms 

The discontinuation symptoms that children and adolescents may experience when withdrawing from an antidepressant are not well studied. In 2011, researchers concluded that children and adolescents may suffer “discontinuation symptoms that can be mild, moderate, or severe,” and that the “essential features of the discontinuation syndrome may not be significantly different than in adults.”

In surveys of adult users of antidepressants, more than half of the respondents have told of experiencing withdrawal symptoms when coming off the drugs, which they often rated as “severe.” Clinical studies assessing this risk have reported that a lower percentage of patients experience such withdrawal difficulties, and that the risk varies greatly depending on which antidepressant the person had been taking.

More than 50 discontinuation symptoms have been described, which collectively tell of a broad disruption of body and mind. They can be categorized in the following way:

Source: S. Hosenbocus. “SSRIs and SNRIs: A review of the discontinuation syndrome in children and adolescents. J Can Acad Child Adolesc Psychiatry 20 (2011):60-67.

 

For children and adolescents, the SNRI venlafaxine (Effexor) and paroxetine (Paxil) appear to be the most problematic antidepressants to withdraw from. Neither of those drugs is licensed for pediatric use in the United States but may be prescribed off-label.

There are wildly disparate reports on how long such withdrawal symptoms typically last. Four studies that researched this question reported a “mean duration” of symptoms that ranged from a low of five days to a high of 79 weeks. There are also many personal anecdotes of  withdrawal syndromes that have continued indefinitely, which has raised concerns that these symptoms are evidence of permanent damage to their nervous systems.

PSSD 

Antidepressants are known to cause sexual difficulties, or dysfunction, in a significant percentage of adult patients. Such sexual difficulty may persist after drug withdrawal, which is a condition that has been labeled PSSD: post-SSRI sexual dysfunction. Those suffering from PSSD complain of genital numbing, loss of libido, difficulties getting aroused, pleasureless orgasms, and other oddities. They also regularly tell of being emotionally muted in other areas of their lives, a symptom that is a hallmark of drug-induced tardive dysphoria.

The incidence of PSSD is unknown, although there is anecdotal evidence—and evidence from rat studies— that suggest it may pose a particularly high risk to those exposed to antidepressants as teenagers, with the thought that the drug exposure interferes with normal sexual development during a “hormonally transformative” time.  Rats reach puberty 45 days after birth, and when male rats are exposed to an SSRI during adolescence (days 25 to 60), they end up with “impaired sexual copulatory behaviors in adulthood.” They mount females less frequently, they are anxious in their behaviors, and when they do mount females, they take a longer time to ejaculate.

The biology of PSSD is unknown, but one thought is that is related to the drug-induced desensitization of the serotonergic system, which then fails to renormalize in some patients following drug withdrawal. It may last for a short period, for several months, or indefinitely, and the severity of such dysfunction appears to range from a mild “I just don’t feel like I used to,” to severe dysfunction that leads to younger adults feeling “asexual.”

Other long-term concerns

PSSD is the most notable example of concerns about possible long-term harm resulting from exposure to an antidepressant during childhood and adolescence. In one review of animal studies, researchers concluded that antidepressants may cause neuronal damage, cell death, and neuronal “dematuration,” which means that “mature” neurons “revert to an immature state.”

Summing Up the Evidence

There are a number of reviews in the psychiatric literature that, by relying on the positive results reported by pharmaceutical companies of their pediatric trials of antidepressants,  recommend judicious use of these agents in children and adolescents. However, researchers that have reviewed the actual study data, and sought to flesh out the harms of these drugs in children and adolescents, have come to a different conclusion. As a 2004 editorial in The Lancet stated, these drugs are “both ineffective and harmful in children.”

 

For more info:

Book: Anatomy of an Epidemic, pages 229-246.

Documents: Review of studies from Anatomy of an Epidemic

Slide presentation: “Medicating Children: Science, Commerce, and Long-term Outcomes.”

Video Presentation: Psychotropic Drugs and Children

Research news and blogs from madinamerica.com

Copyright: Mad in America Foundation, 2019