02/8/22

Are Antidepressants Worth the Risks?

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Business Insider published an article in 2016 with some startling statistics on the global use of antidepressants by the Organization for Economic Cooperation and Development (OECD). They discovered that in all 25 countries, antidepressant use was increasing. “The increase in antidepressants consumption has spurred an ongoing debate [about] whether antidepressants are overprescribed (medicalization) or underprescribed (poor access to treatment).” The U.S. was not included in the OECD analysis, but if it had been, it would have topped the list, as the following chart indicates.

The chart suggested that 11% of Americans, 110 per 1,000 people, used antidepressants in 2016. But the use of antidepressants is not an accurate indicator of depression rates. In the U.S., for example, only about one third of people with severe depression take an antidepressant. Yet the use of antidepressants is rising.

The CDC reported that 13.2% of American adults used antidepressants in the past 39 days. Antidepressant use increased with age, from 7.9% among adults aged 18 to 39 to 19.0% for those aged 60 and over. Use was higher among women than men. Almost one-quarter of women aged 60 and over (24.3%) took antidepressants. See the follow figure from the CDC data brief.

The History of Antidepressants

Given the increased use of antidepressants globally and within the U.S., it seems some awareness of the history of antidepressants and their potential side effects would be helpful. In an article for Psychology Today, Mark Ruffalo gave a brief history of antidepressants in his discussion of Prozac (fluoxetine). He saw the introduction of that drug in 1987, the first SSRI, as a “game changing” event in the history of psychiatry.

The search for a drug to specifically target depression began in the 1950s and led to the monoamine hypothesis of depression. The monoamine hypothesis suggested depression was associated with a deficiency in the monoamine systems of serotonin, noradrenaline and dopamine. In the 1960s and 1970s, psychiatry believed norepinephrine played a central role with affective disorders. “Serotonin’s role was minimized and seen only as ancillary to norepinephrine.”

Tricyclic antidepressants such as Tofranil (imipramine) and Elavil (amitriptyline) were brought to market. They block the reabsorption (reuptake) of serotonin and norepinephrine, increasing the levels of these two neurotransmitters in the brain. But there are side effects such drowsiness, blurred vision, constipation, dry mouth, light headedness, sexual problems, and others. Given the multiple adverse effects, tricyclics were only prescribed for the more severe cases of depression. But that all changed with Prozac.

In the early 1970s, the pharmaceutical company Eli Lilly began to investigate the possibility of developing an antidepressant drug that avoided the potential cardiovascular risks associated with some of the earlier tricyclic antidepressants (like imipramine and amitriptyline). The Lilly team, which included the Hong Kong-born biochemist David Wong, synthesized several chemicals derived from an antihistamine called diphenhydramine (found in Benadryl and over-the-counter sleeping aids like Tylenol PM). Wong, who was familiar with European research implicating serotonin in mood regulation, encouraged the team to screen their newly synthesized chemicals for any that might selectively inhibit the reuptake of serotonin. On July 24, 1972, they found one [fluoxetine].

A few years later, Eli Lilly filed an application with the FDA to investigate fluoxetine’s potential to treat clinical depression. Ruffalo said initial expectations were modest. In December of 1987, fluoxetine, now branded as Prozac, received FDA approval. “Within a few months, Prozac sales outpaced the market leader Pamelor (a tricyclic), as physicians believed that Prozac was both safer and avoided the weight gain common with the tricyclics.” Prozac became the best-selling antidepressant of all time.

With Prozac’s mass success, a new type of depressed patient emerged: the mildly depressed. For hundreds of years, depression (historically termed melancholia), was considered a rare and serious disease, usually only observed in psychiatric inpatients. Because Prozac was so safe—and the risk of drug-drug interactions minimal—doctors began prescribing it to patients with milder symptoms, those to whom they might have hesitated to prescribe a tricyclic. Patients who would have been treated in psychotherapy instead started on Prozac. A biological revolution was well underway.

More SSRIs (selective serotonin reuptake inhibitors) came to market. Zoloft (1991) and Paxil (1992) were followed by the release of the so-called SNRIs (serotonin-norepinepherine reuptake inhibitors) such as Effexor (venlafaxine, 1993) and Cymbalta (duloxetine, 2004). Pfizer, the manufacturer of Zoloft, spearheaded the claim in drug advertising that a “chemical imbalance” caused depression, which SSRIs like Prozac and Zoloft corrected.

In 1993, Peter Kramer published Listening to Prozac, which became a New York Times bestseller. In addition to lifting depression, he suggested these new drugs could be used as personality enhancers. “Kramer raised the possibility that, in addition to lifting depression, Prozac could also brighten a dull personality, assist an ambitious employee in climbing the corporate ladder, and make a shy person lively and outgoing.” Public interest in the drug piqued, and in 1993 sales increased 15%. At this point in time, SSRIs are the first-line pharmacotherapy for major depression, anxiety disorders, obsessive-compulsive disorder and post traumatic stress disorder.

SSRI antidepressants are now one of the three most commonly used therapeutic classes of drugs in the U.S. And their long-term use has been steadily increasing as well. In 2014 the CDC reported that 68% of persons who used antidepressants had done so for 2 years or more; 19% between 5 and 10 years; and 25.3% had been using antidepressants for 10 years or more. See the figure below.

The Consequences of Overprescribing Antidepressants

The popularity of antidepressants has led to concern that they are being overprescribed. Allen Frances, who is a Professor and Chair Emeritus of the Department of Psychiatry, Duke University, noted that most antidepressants are now off patent and their popularity cannot be attributed to the marketing of pharmaceutical manufacturers. He said general practitioners, not psychiatrists, write most of the prescriptions.

Often they must do so after rushed visits with patients they don’t know very well; who frequently present on one of the worst days of their lives; with nonspecific symptoms of stress, depression, or anxiety. The quickest way to get a worried patient out of the consulting room is to write a prescription.

Research has shown that between one-third and one-half of patients taking antidepressants long-term have no evidence-based reason to be using them. Frances said there are two reasons patients stay on antidepressants who don’t really need them. The first is because of misattribution. Someone who feels better after starting antidepressants will likely assume the pills caused the improvement—not realizing that most mild symptoms are stress-related and are likely to go away on their own. “Stopping pills that never were, or are no longer, necessary is hard to do once the person believes they have worked.”

The second reason people stay on antidepressants long-term is because of the withdrawal symptoms that occur when these medications are stopped too abruptly, after prolonged use and at higher doses. These symptoms can include: lethargy, sadness, anxiety, irritability, trouble concentrating, sleep problems, nightmares, nausea, dizziness, and strange sensations, like brain zaps. They can also continue for a long time. Frances cited a report to the All-Party Parliamentary Group for Prescribed Drug Dependence, which said:

The available research shows that antidepressant withdrawal reactions are widespread, with incidence rates (i.e. the percentage of antidepressant users experiencing withdrawal) ranging from 27% to 86%, and with nearly half of those experiencing withdrawal describing these reactions as severe. Available research also indicates that withdrawal effects are not ‘self-limiting’ (i.e. typically resolving between 1-2 weeks). Rather, between approx. 25% of users experience AD withdrawal reactions (such as raised anxiety) for at least 3 months after cessation, with many experiencing AD withdrawal for longer than 6 months.

Another Psychology Today article titled, “An Epidemic of Antidepressants,” said the beneficial evidence for antidepressants was ambiguous and there is increasing evidence that their risks have been underestimated. The author suggested the fundamental reason why antidepressants are so widely prescribed is that they fit the ‘medical model’ of mental illness, now the standard view in western culture.

This model sees depression as a medical condition which can be “fixed” in the same way as a physical injury or illness. In a more general way, this fits with our culture’s materialistic assumption that the mind is just a product of the brain, and our mental functioning can be entirely explained in terms of neurological factors.

This is a simplistic and dangerous way of viewing depression, which the overuse of antidepressants shows.  Noted by the author, there are many other contributing factors to depression, such as: an unsatisfactory social environment, relationship problems, the frustration of basic needs (for self-esteem, belonging, or self-actualization), a lack of meaning and purpose in life, oppression or unfair treatment, negative or self-critical thinking patterns (related to low self-esteem), a lack of contact with nature, poor diet, and more.

Lack of Evidence for Antidepressants

As it turns out, the evidence for the effectiveness of antidepressants seems to have been exaggerated. In 2018 a study published by the University of Oxford reviewed over 500 international trials and found a consistent benefit of antidepressants to placebos. However, the study used the Hamilton Depression Scale on which participants overall score can range from 0 to 52. Antidepressants only reduced the severity of depression an average of less than 2 points, which is not clinically relevant. See “The Lancet Story on Antidepressants, Part 2” for more on this.

A 2008 meta-analysis by Irving Kirsch showed no significant difference between leading antidepressants and placebos. The findings of this study have been reproduced several times, and cannot be easily dismissed. He found that 82% of the response to antidepressants was due to placebo. See  “Listening to Antidepressants” and “Dirty Little Secret” for more on Irving Kirsch and his research.

Researchers who analyzed the data for all randomized placebo-controlled depression drug clinical trials submitted to the FDA found that almost half (49%) had no significant improvement over inert placebos. Whether the studies were published and how the results were reported were strongly related to their overall outcomes. Of the 36 studies whose results were negative or questionable, only 3 were published as not positive. Twenty-two were not published and 11 (in the opinion of the researchers) were published as having positive results, when the FDA thought their finding were negative.

The evidence for the benefits of antidepressants is ambiguous, while their risks have been minimized. “It is well known that SSRIs may have some significant side effects, such as fatigue, weight gain, emotional flatness, loss of libido, insomnia, and agitation.” This raises the question of whether the continued use of antidepressants is worth the risks for the vast majority of those who use them.

11/22/16

Antidepressant Misuse Disorder

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Chances are you know someone who is using an antidepressant. But that doesn’t necessarily mean the person you know has a problem with depression. In 2015, Takayanagi et al. published a study in The Journal of Clinical Psychiatry found that: “Among antidepressant users, 69% never met criteria for major depressive disorder (MDD); and 38% never met criteria for MDD, obsessive-compulsive disorder, panic disorder, social phobia, or generalized anxiety disorder in their lifetime.” Their data indicate that antidepressants were commonly used in the absence of “clear evidence-based indications.”

Writing for Mad in America, Justin Karter noted that previous studies revealed antidepressants were being over-prescribed and prescribed off-label. But others countered that these studies underestimated the lifetime prevalence of so-called mental disorders. The Takayanagi et al. study sought to address this criticism by conducting in-depth interviews to estimate whether participants met criteria for “mental disorders” over their lifetime. The study also indicated an individual was more likely to be prescribed an antidepressant if they were a woman, white, reported physical pain or discomfort to their doctor, or had recently visited a mental health care facility.

Another 2015 report by Kanton et al. published in JAMA found that the percentage of Americans on antidepressants increased from 6.8% to 14% between 1999 and 2012. The report’s authors speculated that the increase could in part reflect shifting attitudes regarding depression. Commenting on this report, Justin Karter pointed out how the increase likely includes a large proportion of off-label use of antidepressants. As was noted above, 69% of antidepressant users did not meet the criteria for major depression.

A JAMA study published in May of 2016 by Wong et al. found that 45% of the prescriptions given for antidepressants were to treat anxiety disorders, pain, insomnia and various other conditions. The study, which was done in Quebec Canada, looked at all adult prescriptions written for antidepressants (100,000 patients) between January 1, 2006 and September 30, 2015. Prescriptions for monoamine oxidase inhibitors were excluded. Prescriptions were classified as on or off label depending upon whether the drug was approved by Health Care of Canada or the FDA for the indication noted by September 0f 2015. Physicians prescribed antidepressant off-label for anxiety disorders (18.5%), insomnia (10.2%), pain (6.1%) and panic disorders (4.1%).

An online survey of long-term antidepressant patients by Cartwright et al., published in Patient Preference and Adherence, found that almost 90% reported some degree of improvement, with 30% also saying they had moderate to severe bouts of depression during treatment.  Ten different adverse effects were reported by over 50% of the participants. The five most common were: withdrawal effects (73.5%), sexual dysfunction (71.8%), weight gain (65.3%), feeling emotionally numb (64.5%), and failure to reach orgasm (64.5%). “Between 36% and 57% of respondents experienced these adverse affects at either a moderate or severe level.” Additional adverse effects reported included: agitation (55.1%), feeling not like myself (54.4%), reduced positive feelings (45.6%), caring less about others (36.4%), suicidality (36.0%), and feeling aggressive (31.6%).

Some patients in this study were particularly concerned about severe withdrawal symptoms that undermined their confidence to discontinue should they wish to and therefore limited their choices. In line with this, 45% patients also believed that they had some level of addiction to the antidepressant. Some patients were also critical of the lack of information given by prescribers with regard to adverse effects, including withdrawal symptoms. Some also expressed disappointment or frustration with the perceived lack of support available to them in managing withdrawal.

Limitations of the study include the fact that the data were self-reported and that the study was not a randomized control study—the gold standard methodology for evidence-based medicine. However, there are relatively few long-term outcome studies of antidepressant use.

A 2009 systematic review published in the Journal of Affective Disorders, concluded that long-term outcomes in depression were poor, with no clear relationship between drug treatment and positive outcomes.  The outcomes for non-antidepressant treatment were no worse than those for antidepressant treatment.

Overall 40% to 85% of patients experienced a recurrence during follow-up. Average time to recurrence was around 3.2 years across eight studies that provided data on this outcome. Around 25% of patients achieved a global rating of well or improved at the end of the study and a similar number had a poor outcome marked by multiple recurrences or continuous impairment. Most participants recovered from the index episode, but experienced multiple recurrences.

The August 2016 issue of Psychotherapy and Psychosomatics published a literature review of long-term use of newer generation antidepressants (i.e., SSRIs and SNRIs and others) by Carvalho et al. While many side effects were transient, disappearing after a few weeks, other potentially serious adverse events may persist or occur later. The main adverse events related to using newer antidepressant drugs included the following:

  • Gastrointestinal issues
  • Weight gain and metabolic disturbances
  • Genitourinary issues (issues related to the genital or urinary organs)
  • Sexual dysfunction
  • Hyponatremia (low sodium level in the blood)
  • Osteoporosis and risk of fractures
  • Bleeding
  • Central nervous system issues
  • Sweating
  • Sleep disturbances
  • Affective disturbances
  • Suicidality
  • Discontinuation syndromes

You can read more information on the above adverse effects and others in the Carvalho et al. review. What follows is a brief discussion of their findings for weight gain and diabetes, bleeding, sleep disturbances, affective disturbances, suicidality, and discontinuation syndromes.

Several studies have shown that long-term use of antidepressants (more than 6 months) is associated with weight gain. Paroxetine (Paxil) may be the worst offender. A population-based study indicated the use of antidepressants could be associated with a higher risk of obesity. The association between antidepressants and diabetes mellitus is inconclusive. Some reports indicate a higher risk; others do not. But a recent review and meta-analysis found that SSRIs were associated with an increased risk of diabetes mellitus.

All SSRIs have been associated with an increased risk of bleeding. “The most likely mechanism responsible for these adverse reactions is a reduction of serotonin reuptake by platelets.” Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) have a higher risk of platelet dysfunction than other SSRIs. Veniafaxine (Effexor) and mirtazapine (Remeron) have been associated with an increased risk of bleeding. SSRIs have been associated with a higher risk of bleeding during operations.

Sleep disturbances are one of the hallmark symptoms of depression. However,  studies have shown that SSRIs and Effexor are associated with increased REM sleep latency and an overall reduction in the time spent in REM sleep. These effects are usually associated with the initial period of treatment and may return to baseline after 8 weeks. Remeron and trazodone have been associated with improving sleep. In my clinical experience, trazadone is regularly used off-label to help promote sleep.

Many individuals taking SSRIs report they experience emotional blunting. They say their emotions have been “toned down.” Others say they just don’t care about issues that were significant to them before. “Evidence indicates that these adverse affective manifestations may persist even after the symptoms of depression have improved and can occur in patients of all ages.” Mania or agitation can occur. These response have been said to unveil unrecognized bipolar disorder. But since this can also occur in previously unipolar patients, the mania could be drug-induced. An activation syndrome, where patients experience anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness and impulsivity can occur.

Carvalho et al. limited the occurrence of these adverse effects to the first three months of treatment. However, psychiatrist Peter Breggin has documented the emergence of agitation and activation with antidepressants in Medication Madness and other writings. Carvalho et al. said using antidepressants could also be associated with the return of depressive symptoms during baseline treatment, and the appearance of new symptoms or paradoxically, exacerbate the baseline clinical picture. The occurrence of paradoxical effects was reported in random control trials with Prozac and Zoloft.

The emergence of suicidality and self-injurious behavior with antidepressant treatment is one of the most debated and controversial risks. Nevertheless, the FDA has required a black box warning regarding the risk of suicidality for children and adolescents using antidepressants since 2014. The incidence of successful and attempted suicide has been frequently underreported in antidepressant RCTs. Carvalho et al. said:

Two recent meta-analyses have not identified a clear increased risk of treatment-emergent suicidality in adult individuals treated with antidepressants in RCTs. Notwithstanding that the use of antidepressants is efficacious for the treatment of MDD in adults, there is no clear evidence for either specific protective effects or increased risk related to suicidality.

Often underappreciated, is the emergence of withdrawal symptoms of varying degrees with treatment discontinuation and/or interruption with almost all SSRIs and SNRIs. These reactions have been described as “discontinuation syndromes” in an attempt to avoid the suggestion of dependence that could effect marketing. A review suggested the dependence and withdrawal with newer antidepressants was comparable to those experienced with benzodiazepines. “Due to the severity and unpredictability of these manifestations, it has been recently suggested that the term ‘discontinuation syndrome’ should be replaced by ‘withdrawal syndrome.’” These symptoms can include:

flu-like symptoms, tremors, tachycardia, shock-like sensations, paresthesia, myalgia, tinnitus, neuralgia, ataxia, vertigo, sexual dysfunction, sleep disturbances, vivid dreams, nausea vomiting, diarrhea, worsening anxiety and mood instability.

In their conclusion, Carvalho et al. said the common belief of fewer side effects with the newer generation antidepressants (especially the SSRIs) only pertains to their safety in overdose. “On the contrary, the long-term use of SSRIs and SNRIs is likely to yield important side effects.” The likelihood of treatment-emergent adverse effects is related to the duration of antidepressant treatment—particularly with weight gain, diabetes, and osteoporsis. Some adverse side effects may persist long after discontinuation of the drug. Particularly following long-term use, antidepressants,

 … may increase the risk of experiencing additional psychopathological (e.g. treatment emergent affective switches and paradoxical symptoms), or medical (e.g. obesity and bleeding) problems that do not necessarily subside after discontinuation of the drug.

This leads to their conclusion that: “The findings of this review suggest that long-term treatment with new generation ADs should be avoided if alternative treatments are available.”