When Owen Muir gets dressed in the morning, he knows exactly what his outfit will look like. First, a suit-wool, pin striped maybe, to put on the air and authority of a doctor that will put parents at ease. But more important than the suit are the accessories-blue Lego shaped cuff links, pink zebra striped socks, and some hip limited edition studded John Varvatos Converse to show the kids that he works with that he’s not just a doctor-he’s a “cool” doctor.
Though most doctors might hold the opinion of parents at a higher level than that of their kids, Muir works hard to make sure that it’s his young patients that trust him and want to open up to him. After all, he really needs to know what’s going on in their lives to ensure that medication is the proper treatment to tackle their depression.
Muir is a resident physician at the Child Study Center at NYU Langone Medical Center and is responsible for diagnosing and treating dozens of children and teenagers with psychological issues. One of the conditions he most often treats in these young patients is depression, a condition that more often than not results in a prescription for antidepressants.
Muir knows what it takes to make a connection with his young patients but despite his extensive training and experience diagnosing teenagers he’s never entirely sure that the medications he prescribes are the best solution to their problems.
“The problem isn’t what antidepressants do to kids, the problem is we don’t know,” he said in reference to the many ways in which the current information we have on SSRIs fails to give us a clear picture of what they do and don’t achieve.
Selective Serotonin Reuptake Inhibitors, SSRIs, are more widely prescribed than ever but despite the fact that they’ve had their place in American medicine cabinets for nearly three decades, little is known about how they affect a very vulnerable and widely using population-teens.
According to a report released by the National Health Center for Health Statistics in 2011 (the latest of its kind) 11 percent of Americans aged 12 and over are currently on antidepressants. This number is alarming given that current methods for establishing the safety of antidepressants on teenagers shed little light on the efficacy and long term effects of these drugs.
First of all, the studies that we have to establish the efficacy of SSRIs in teens are underpowered, meaning that they generally have small samples, especially given the large number of teens suffering from depression in the general population. Larger studies are needed not just to be able to generalize results but also because suicide, the most drastic negative side effect associated with antidepressants, is a rare event, meaning that the smaller the sample is, the less likely you are to see effects of SSRIs on suicides.
Additionally, by design, these studies prohibit suicidal patients, that is, the ones with the most severe cases of depression who stand to benefit the most from this research, from participating. This is done out of the ethical concern of assigning a severely depressed teen to a placebo but it still leaves us with no hard facts about how effective these drugs really are.
Aside from suicide, studies on SSRIs generally fail to look at perhaps more common and important effects that result from taking SSRIs-are they actually helping teens function day to day? The big emphasis is on rating scales-questionnaires designed to assess severity of depression and recovery- and whether or not participants are showing signs of improvement by increasingly changing their scores on these measures. A commonly used scale is the Hamilton Rating Scale for Depression (HAM-D) which assesses depression by asking about things like mood, feelings of guilt, suicidal thoughts, and somatic symptoms. The scale is administered by a doctor and based on their answers, patients are given a score that indicates if their depression is changing. But as Muir points out, numbers on a scale don’t mean anything to a teen that has to muster the power to get out of bed every morning.
“What outcomes matter to patients? Do they care that they’re 3 points lower on a rating scale? No! Do they have a life they can live? Well, yeah, that matters,” he said.
Something that studies on SSRIs have established over and over again is that antidepressants have a high placebo effect, meaning that you could take a sugar pill and probably do just as well as on an SSRI- plus spare yourself the side effects.
Despite this trend that appears in a lot of the literature, Muir insists that in his experience, pills are still incrementally better than doing nothing.
Some depressed teens who have taken pills however, might disagree.
Chris Felix, 22, is a senior at New York University where he’s majoring in psychology and minoring in music. Felix may have a tall and commanding presence but he also has friendly hazel eyes peering out from behind thick glasses and a warm contagious smile that makes everyone want to talk to him-something he thoroughly enjoys. In fact Felix is above all social-his favorite thing to do is host and DJ parties to bring all of his many friends together and to give him the satisfaction of making them happy. But this fun, carefree version of Felix is entirely different from the 18 year old that first arrived in New York. Felix vividly remembers his freshman year of college as constant chaos despite the many pills he tried to alleviate his feelings of stress and depression.
“You know that feeling you have when it’s finals season and you’re just always on edge? Just like that, constantly and no matter what I was doing…things I enjoyed, singing, playing sports, going to the gym, hanging out with people-just doing those things I was feeling stressed constantly, and they just weren’t doing anything for me,” he said.
Felix was constantly putting pressure on himself to do better, to do more, but nothing ever satisfied him. Even the most mundane thing like hanging out with friends became a complex situation that could be changed-he could do better at it.
His dissatisfaction with every facet of his life pushed him to finally go to therapy. His first therapist was alarmed by how his condition seemed to worsen in the three days between their first meeting and their follow up to the point where she felt “uncomfortable” letting him leave her office. What ensued was not hospitalisation, at least not right away, but a constant jump from therapist to therapist and pill to pill.
If you ask him what they put him on, he can’t recall every prescription. It started out with Lexapro, then another one that made him gain 20 pounds in three weeks despite the fact that he played rugby and worked out regularly. The next one made the weight gain continue. The one after that gave him erectile dysfunction and the one after that made him “orgasm after three seconds.” Then somewhere in the mix was Prozac which didn’t do anything in terms of side effects but also didn’t do anything as an antidepressant, “it was just nothing.”
If antidepressants are supposed to be better than placebo at treating the symptoms of depression, Felix was not convinced.
“Going through depression, medication, all that–it was very frustrating to me. Either because it wasn’t working, or what was happening was also having negative side effects… I didn’t feel like I was winning at anything,” he said.
The worst problem was that by trying to help his depression and continually failing, the feelings of helplessness that drove Felix to medication in the first place, intensified.
After going through what seemed like an endless series of pills and shrinks, Felix decided that suicide was the best option for him-he didn’t feel bad about it, to him “it felt right”. He chose to go through with it by taking “a whole gym bag of pills,” every bottle of meds he’d ever been prescribed, every last little pill that he could find, he swallowed it down and then waited to die. But he didn’t die-he woke up in excruciating pain and felt like his insides were burning, but he was alive and rather than go to the hospital or call 911, he dragged himself to chemistry-even on the brink of death he had to be a good student.
It wasn’t until later that day when he showed up for his weekly therapist appointment that he finally got medical attention. After checking his heart rate and blood pressure-they were so high it was shocking that Felix hadn’t died-his therapist promptly sent him to the hospital. The one thing Felix had tried to avoid throughout his battle with depression was hospitalization, but after his suicide attempt he had no choice. As mandated by NYU, he spent two weeks in the hospital and another two weeks in an outpatient program, until his doctors, his parents, and the school were convinced he wasn’t a threat to himself.
After his hospitalization, Felix swore off pills. They may be the difference between life and death for many people but for him, they weren’t.
“It was a lot of trial and error. And at the end, I was just like, medication is just not working for me…This isn’t a valuable method of treating this depression.”
Peter Simons, a writer for Mad In America, an online magazine that examines psychiatric news, and a candidate for a PhD in counseling, says that cases like Felix’s, where antidepressants turn out to not be a magic solution, aren’t all that uncommon.
“I’m going to get my PhD, not an MD, and that was a deliberate choice that I made because I don’t buy into the pharmacological narrative of how to alleviate suffering,” he said.
Simons’ view, and that of the majority of the writers at Mad in America, is that our cultural reliance on drugs to cure psychiatric illnesses has failed us and that we should be looking to alternative forms of treatment, primarily, therapy.
According to Simons, the studies that are done to ensure the safety of SSRIs typically only serve to establish that these medications have a better effect than a placebo-a dummy pill with no active ingredients-and evaluate little else. Proving that a drug is statistically better than a placebo at eliminating markers of depression means that it can get Federal Drug Administration (FDA) approval-the sole goal of pharmaceutical companies.
One of Simon’s recent articles is about a study by Janus Christian Jakobsen at the
Centre for Clinical Intervention Research at Copenhagen University that analyzed 131 randomized control trials of antidepressants to evaluate their efficacy. The study found small benefits of using SSRIs in depressed patients- 1.29 points on the HAM-D for mild to moderately depressed patients and 2.69 points for severely depressed patients which according to Simons is “very little evidence of [antidepressants] actually working much better than placebo.”
The reason for this is that a lot of what is measured by depression rating scales are somatic symptoms, in other words, sleeping and eating habits. A decrease in your HAM-D score signifies improvement, so theoretically getting a low score would imply that your depression is improving but this low score might be capturing your increase in sleep, or a normalization in your appetite–not a decrease in actual depressive symptoms.
“So that will look like, ‘oh, that’s a better effect-you have less depression’ when really it has nothing to do with your mood, your feelings of worthlessness, suicidality. It might not be improving any of those things and it could be making those things worse and still be offset by sleeping and eating effects and so it looks better on that measure than placebo,” he said.
Another reason why we might think that antidepressants are more effective than they actually are is due to the biggest flaw of the medical world, publication bias.
Publication bias refers to the idea that the outcome of a study is what determines whether it is published or not. That is, if a study proves what researchers want it to prove, it’s going to get published-if it doesn’t, it’s likely that no one will ever know it happened. Given the years and money that pharmaceutical companies invest developing a drug that will return a profit, they will only publish results that are favorable to them.
So how can pharmaceutical companies get a new drug approved by an agency like the FDA when the there’s studies that show it doesn’t work? Well, because they just don’t submit those studies.
When a pharmaceutical company develops a new drug and wants to get it on the market, they are responsible for providing their own evidence that their drug is better than placebo and statistically significant. Once they have a couple of studies that do this, they can submit these to different government agencies, like the FDA, in whatever countries they want approval. The government agencies then go over the data and determine whether or not to allow the drug on the market.
Essentially, the FDA doesn’t test new drugs on their own-they rely entirely on the data provided by pharmaceutical companies. While the FDA requires more data to be submitted for approval than other government agencies like its European counterpart, the European Medicine Agency, pharmaceutical companies can still get away with only submitting favorable data and hiding negative details in appendices that generally go unread-more on this shortly.
“As long as you provide a couple of studies that show your drug is more effective than placebo, and it’s statistically significant-even if it might not be clinically significant-it seems like that’s good enough,” said Simons.
With this system, what doctors and the general public often get are studies that paint SSRIs favorably and while they may concede that some people experienced an increase in suicidal thoughts, or had worsening depression, little else is said about other side effects such as increased aggression and sexual problems. It isn’t until later, once the approval process has passed, the drug is on the market, and people start not responding in the way that was expected that we find out a drug isn’t the miracle it was made out to be.
A recent meta-analysis by researchers at the Nordic Cochrane Center in Copenhagen demonstrated how publication bias in the antidepressant literature has minimized the impact that these drugs can have on teenagers.
The meta-analysis looked at clinical study reports, which are detailed accounts of what actually happened in a study complete with appendices and figures, versus the more polished and thinned out results that actually get published and submitted to government agencies and the general public. The discrepancies between the complete information in the clinical study reports and what actually made it to print were astounding.
“If you looked at the [published study] it didn’t look bad…while the reality was quite different,” said Tarang Sharma, one of the researchers that put together the meta-analysis.
Sharma and the other researchers found that many studies on the efficacy of antidepressants under-reported attempted suicides and increased suicidal behaviors by passing off the events as “worsening depression” or “emotional liabilit[ies]” as opposed to calling things like they were. According to Sharma, it’s common practice for pharmaceutical companies to create coding dictionaries and pass off unfavorable behaviors in more positive terms.
What’s more, many negative events were hidden away in appendices that government agencies weren’t likely to scrutinize.
“It’s the job of the regulator to read the whole document but a lot of stuff is pushed into appendices and then the expert committees don’t have much time or resources to devote to the documents,” said Sharma.
By hiding this information without actually destroying it, the companies are covered from liability-despite grossly downplayed the severity of negative events associated with their drugs.
The same study also found that published results on Eli Lilly’s website (the makers of Prozac) were more unreliable in reporting adverse effects than they had suspected, in fact, “only mortality had (almost) complete information.”
However, the most important findings of the meta analysis weren’t even related to under-reported adverse effects in adults, but rather, on children and adolescents.
A closer look at the clinical study reports analyzed by the Nordic Cochrane Center showed that studies involving minor’s increases in suicidal ideation and aggression were more significant than in those involving adults. In fact, their findings showed that suicidal actions and aggression in children and teens doubled during clinical trials. These effects were unreported in the accompanying published studies.
What’s more, because the European Medicines Agency (EMA) had given their Prozac study data to the Medicines and Healthcare Products Regulatory Agency (MHRA-the FDA’s British counterpart) and the MHRA destroyed most of it due to storage policies- the researchers only had access to three Prozac studies. Given that Prozac is widely used by teens and children, and that there have been more than three studies conducted with it, this missing data might have revealed even more hidden effects of antidepressants on teens-but we’ll likely never know what they were.
According to Sharma, getting access to any of this data was a lengthy and difficult process that became a legal battle between the EMA, pharmaceutical companies, and the ombudsman working on behalf of the public. Thanks to this battle however, all new and old drug trials will eventually be made available to the public. The FDA, as of now, has no similar policy.
The findings of these researchers show that the amount of bias in published studies is striking when compared to what actually happens during clinical trials of a drug. The marked effects that antidepressants had on teens and antidepressants for example, is contrary to the narrative of the published studies we have.
What’s frightening is that given the incomplete data that the researchers had to work with, the total effect of these drugs may be worse than what they found.
What the meta analysis (and most studies in general) didn’t look at, but is still a marked side effect of SSRIs, is sexual dysfunction. Of course, sexual side effects seem miniscule when compared the potential of these drugs to lead people to suicide, but as Muir would emphasize, quality of life is also important.
It’s well established that SSRIs cause sexual side effects. Things like reduced libido, inability to orgasm, premature ejaculation, and even erectile dysfunction are well documented in adults. According to Simons, a recent Medscape survey of 1000 people on SSRIs found that 88% of them had some form of sexual dysfunction.
Of course, it can be argued that some of the sexual problems that are seen in depressed people may be the result of depression itself-it’s hard to feel sexy when you’re overwhelmed by feelings of despair and hopelessness. But there’s plenty of evidence that shows SSRIs either cause or worsen these symptoms. Even worse are the indications that sexual side effects persist even after a person stops taking medication.
The question then becomes, if these problems are common in adults are they also common in teens? And if so, what’s the risk of these problems becoming long term issues when a teenage body is still in development?
Here is where data is lacking. There’s an indication from animal models that teenage exposure to SSRIs can cause long term sexual dysfunction. One rat study by Sergio D. Iniguez and his team at Florida State University for example, found that teenage rats that were treated with Prozac had impairments in their sexual lives as adults.
The rats were treated with Prozac for 15 consecutive days from 35 to 49 days old (teenage years in rat time) and were compared to rats that didn’t receive treatment until adulthood. Rats treated as teens suffered from mount latency (they took a long time to want to engage in sexual behavior), a long time to climax, and lower ejaculation frequency than their adult peers. Researchers also found that rats in the teen treatment group still suffered from these deficits at 80 and 90 days old (adult years in rat development) even though they had stopped treatment at 49 days. This provides evidence for the idea that teenage exposure to antidepressants may affect a person’s sex life well into adulthood.
The rats also showed that adolescent exposure to prozac led to decreased response to stressful situations like forced swimming or maze exploration and a lessened desire to approach new objects, foods and environments in adulthood. The way these teen-treated rats held back from things that the adult-treated group approached eagerly is consistent with anxious behaviors in humans and indicates that teens that take antidepressants may have a harder time coping with stress.
Now taking findings from rat studies and saying that they have irrefutable implications for humans would mean taking a huge leap. But it would seem irresponsible to ignore the signs that SSRIs and negative, potentially long term, side effects seem to be linked together. Do we have any actual data on how they function in teenagers and how they affect them in the long run?
If you Google studies on teenagers and SSRIs you’ll find one that pairs just about every SSRI with everything from depression to Obsessive Compulsive Disorder. You’ll also find many studies that compare different medications to each other, like Prozac to Lexapro, or different forms of therapy to SSRIs. However, what is incredibly hard to find are studies that follow patients beyond a couple of months and observe how the body responds to medication long term.
One of the few studies to follow its young patients for more than a few weeks is the Treatment for Adolescents with Depression Study (TADS).
Back in 2000, you could find Mark Reinecke engaged in a conference call in his office at Northwestern Memorial Hospital on any given Monday between 1 and 2 pm. This one hour was strategically blocked out every week to accommodate the different time zones of all the scattered researchers dialing in to discuss the latest on their patients progress. Every week Reinecke and some of the best minds from universities all over the country-Johns Hopkins, New York University, Case Western Reserve , U of Oregon, and The University of Texas Southwestern-got together over the phone to discuss how best to serve the patients they were treating for TADS.
“That weekly case conference made me and the other therapists much better therapists because we were getting feedback and recommendations from colleagues from across the country on some very difficult patients,” he said.
TADS was a multi-center study sponsored by the National Institute of Mental Health that compared the short and long term effectiveness of Prozac on teens versus cognitive behavioral therapy (CBT-which focuses on reframing problems and creating effective ways of dealing with stressors) or a combination of both treatments. The study included 439 participants from across the US between the ages of 12 and 17 who had been diagnosed with major depression.
The study was one of a kind because it was naturalistic meaning that it looked at teens in real life settings as opposed to lab settings. It was representative meaning that the sample of teens was reflective of US census data, which in turn meant that the results of the study could be generalized to all US teens. Finally, it was longitudinal meaning that as opposed to most other studies, it didn’t stop assessing patient progress after a few weeks of treatment, rather it followed participants who chose to continue for up to 4.5 years after active treatment was over.
“I’m not aware of anything else like it,” said Reinecke.
Participants were assigned to one of four treatment groups: Prozac alone, CBT alone, Prozac combined with CBT, and placebo. Combined treatment was initially the best and remained the best with a total 86% improvement, but Prozac alone and CBT alone also caught up with 81% of patients improved by the end of the study. Though suicidal thoughts and behaviors did increase in teens on Prozac, no suicides were completed during the study despite having a sample of moderately to severely depressed teens.
The efficacy of combined treatment is nothing new-many studies have shown that it’s generally better to treat depression with both medication and therapy. What was interesting was that once treatment itself was done, many of the TADS participants continued to be assessed and thus gave us a better picture of how treatment and depression pan out over the years.
The follow up period after TADS was over, painted a relatively positive image of what our current treatment options can offer to depressed teens.
This period found that global functioning-that is, functioning in social, occupational, and other areas–remained high or even improved in teens that had been in any of the active treatment groups during TADS. This meant that teens who suffered from crippling depression that may have kept them from functioning normally before were now getting into college, starting careers, and even developing meaningful relationships which Muir would argue is really the goal of treating depression.
The only teens who seemed unable to move beyond their depression and lead meaningful lives were those that had multiple diagnoses and those who had recurrent episodes of depression. This specific sample of teens that was resistant to treatment may have implications for the importance of personalizing treatment-but we’ll get to that later.
TADS was a significant study because it was government funded meaning that pharmaceutical companies didn’t have any control over the study and couldn’t tinker with the results, thus eliminating the issue of publication bias. Its long follow up also gave us a good idea of the effectiveness of different treatments in the long term. Also as Reinecke pointed out, “In our study we had no completed suicides which tells us we can treat depression with medication. This is reassuring.”
However, there are still things that TADS missed-the study didn’t measure aggression or sexual dysfunction. Also, at no point were brain scans done to see how treatment impacted brain development and function-something that could be especially helpful to assess in a brain that is constantly changing.
Finally, though TADS was an ambitious effort that looked at treatment not only in the long term, but also in a relatively large and representative sample, it is just one study. Replication is key in science-your findings don’t mean anything unless someone else can get the same results by following your method-and since SSRIs and the treatment of depression is scientific in nature, we can’t say that TADS answers all our questions about the treatment of adolescent depression. But, given the millions of dollars that it takes to conduct a study of this magnitude (TADS cost $17 million), and the yearly $1.5 billion NIMH budget that is responsible for funding research and projects on all sorts of mental health issues-not just teenage depression-it’s unlikely that we’ll see another study like this any time soon.
When Prozac hit the market in the ‘90s, it was a huge hit. Predecessors to Prozac had established that depression was a treatable disease, as opposed to a character flaw, and given the drug’s ability to work with less side effects than others like it, it became a go-to drug for depressed Americans.
Such wide public interest led not only to the acceptance of Prozac but also to the creation of many more SSRIs. Today, Prozac is no longer the most prescribed antidepressant-its twenty eight million prescriptions in 2013 trail behind Celexa’s thirty nine and Zoloft’s forty one million- but its millions of prescriptions, coupled with those of other SSRIs indicate that we’re still sold on the idea of medication at the expense of trying and investing in other treatment methods.
According to Simons, “there’s this idea of medication seeming more scientific, it feels more scientific to people…it feels like, ‘oh this is medicine’ whereas psychotherapy feels like it’s fake.”
There also seems to be a cultural perception that therapy is just not fast enough.
We seem to have warmed to the idea of SSRIs because they seem more legitimate and relatively faster than spending years on a couch listening to the hmmms and ahhhs of a detached therapist that will only come back at us with the stereotypical, “and how does that make you feel?” But the thing is, other methods exist, and they exist because, at least for some people they work.
Beyond meds we can treat depression with electroconvulsive shock therapy and transcranial brain stimulation in the case of more severe patients but before getting to that point, and maybe even before getting to meds, perhaps we should reconsider therapy.
Muir is a trained psychiatrist. He went to medical school and studied for many years to become a good one, he could have put in just one more year and become a neurosurgeon instead (and earned himself a lot more money) but he chose to become a child psychiatrist. Yet, despite this commitment to psychiatry, Muir will be the first one to tell you that therapy, especially mentalization based treatment (MBT), a form of therapy that integrates a variety of psychodynamic approaches, is actually the best form of treatment for depression.
Muir initially became a psychiatrist because he felt it was the best way to treat his patients, then he did training in MBT and “saw miracles.”
“The data for it is miraculously effective. The effect sizes blow almost every medication out of the water… it’s more potent than any medication for any condition in all of psychiatry. So I became a therapist cause therapy works,” he said.
Muir is of course, not the only person to think therapy is effective-Reinecke and Simons agree. But beyond that, countless studies and personal anecdotes concur that therapy treats the symptoms of depression, but also makes people resistant to falling into a depressive state again.
As we saw, the data from TADS supports this view too-cognitive behavioral therapy in combination with medication worked more effectively and faster than prozac alone. The combination treatment and CBT alone groups also showed the least amount of suicidal thoughts, therefore successfully avoiding the major side effect of SSRIs in teens.
So if we have therapies that work and do so with no side effects why do we not use these more? Because of two important obstacles to its popularity, a lack of good therapists, especially those that treat children, and a high cost that insurance typically won’t cover.
Therapists are in short supply everywhere. This is especially true of places that are not huge cities like New York and LA, in other words, most of the US. According to Muir the reason for this is pretty simple, becoming a child psychologist is hard-it takes a lot of training (one year less than neurosurgery), it’s a lot of work (Muir for example, works 70 hour work weeks), it doesn’t pay well (according to him, a UPS truck driver working his hours would be better off financially) and it involves dealing with a lot of loss.
“Becoming a psychiatrist or psychologist means you agree to carry the burden of someone’s suicide…It means, when someone kills themselves, you’ve gotta fucking deal with that. And that’s not true of being a banker,” he said.
It’s especially frustrating to take on that burden when you know that most people who need access to therapy just won’t get it because at the end of the day, therapy is expensive.
Muir takes a medication that is incredibly effective for his psoriatic arthritis the cost of which is $90. After calling his insurance company he found out that if it weren’t for them, he’d be shelling out ten grand a month for that medication-the medication that works for him.
And that’s the problem with therapy. To get therapy, people have to shell out a figurative 10 grand, because insurance rarely covers a visit to the therapist. A prescription for Prozac? Well, that’s another story.
“If I could inject therapy, it’d be $10,000, and I’d get it covered. Since I can’t, I can’t pay people well enough to learn the therapies, I can’t pay people well enough to become adherent to the therapies, I can’t have families have enough money to afford to get those treatments-and those treatments save lives,” said Muir.
So if the main issue with therapy is that it’s not a magic fast-acting pill and it’s not covered by insurance, are we looking to any other treatments that might be a better fit for our pharmacological model?
Ketamine is a promising alternative to our current medications for depression.
Ketamine is a veterinary and human anesthetic that has been around for a long time and has a pretty clean record. Its best feature is perhaps that it works close to right away, relieving depressive symptoms, even symptoms of suicide, within hours. In 70% of people, depression, including suicidal thoughts and behaviors, is resolved almost entirely. The issue is that researchers still haven’t found a way to sustain the effect. But even so, according to Muir, if he were suicidally depressed he’d get ketamine “right away”.
Simons is a little more skeptical of this “miracle drug” and is not entirely convinced that it doesn’t just have the same effects of other commonly used drugs like, say, alcohol.
Whether Simons or Muir are right in the end, we need more testing before ketamine will ever be taken seriously as a treatment for depression. Whether it’s to establish the right dosage to sustain its antidepressive properties or to determine efficacy and side effects we need more randomized control trials on the substance. But, in order to do trials, you need money and no one has that sort of cash lying around except for pharmaceutical companies which means that the likelihood of ever seeing ketamine packaged into a sellable drug for depression is very low simply because it will never be tested in a way that is satisfactory to the FDA.
“The FDA doesn’t approve things that work. The FDA approves things that have gone through FDA approval trials, there is no reason on earth to give ketamine an FDA approval trial because it’s generic,” said Muir alluding to the fact that a generic drug means minimal profit for pharmaceutical companies. And since big pharma cares about profit above all else, generic translates to “not interested.”
Given that SSRIs work but seem to have a lot of caveats, therapy is too expensive, and it seems like there is little being done to find alternate forms of treatment, it might be worth asking, what are the consequences (or lack thereof) of leaving teenage depression untreated?
“When you’re on the right medication it feels like you’re you,” says Evelyn Derico, a 28 year old writer from Michigan. Derico recently returned to Detroit after a stint in New York where she moved to pursue better writing opportunities. Today Derico lives on her own, is a cat mom to Julius and Kamaji, and produces content for Liquor.com-all things that she’s able to do thanks to the 40 milligrams of Celexa she takes every day.
Derico credits her ability to get out of bed and live a normal life in large part to her meds, but it took a long time for her to start feeling that way.
She remembers the first time she realized she was depressed. It was in a high school psychology class when, her classmate Alex went up in front of the class and talked about her struggle with depression. She explained the effect her parent’s divorce. She described taking a nail file from her mom’s vanity and cutting her wrists. Alex tried several different medications to treat her depression. Everything Alex said resonated with Derico and suddenly she understood why she never felt quite normal. Up until then she had discounted her feelings as normal teenage angst. “That was my moment of clarity where I realized that I definitely was mentally ill,” She says.
Derico began therapy soon afterwards. She liked her therapist. He was a cool adult who wore Chuck Taylors like her, and actually listened to her. But no matter how much he listened, her depression didn’t get better. She started taking Prozac, but it made her feel numb and, after a year and a half, she decided it wasn’t for her.
Then something odd happened: she felt better. “I felt like i could make decisions more clearly about things I actually wanted. It was basically like a fog had lifted. I could feel emotions again, I could cry again,” she said.
Derico decided to do without meds until she started college. She took antidepressants briefly, but they again affected her negatively, and she stopped. Her depression worsened. She began failing classes and was put on academic probation. She couldn’t function on meds, but she also couldn’t function without them.
On April 17th, 2015 her heart began racing And she had trouble breathing. She feared she would collapse at any moment, and felt like she was dying. Emergency room doctors performed a battery of tests, but couldn’t find anything wrong with her. They concluded she’d had a panic attack, and prescribed Xanax
“The whole experience was really terrifying but it needed to happen,” she says. “I kept telling myself I was fine and not dealing with my emotional issues and then one day I was very clearly not fine,” she said.
Now Derico sees a therapist and psychiatrist regularly. Together they finally found that Celexa was the right SSRI for her. She can work, care for her cats, have meaningful relationships. She still occasionally battles depression and anxiety, but she’s better equipped to deal with it. “I need meds because otherwise I would just be sitting in my bed right now shaking and unable to do anything,” she said.
Should we be medicating our kids?
A good way to answer that question is to look at what happens when we stop medicating depressed teens.
Not long after SSRIs were introduced and people outside of pharmaceutical companies got access to the data behind the drugs, concerns were raised about their potential to increase suicidal thoughts and actions. Prozac was of particular concern after an article came out describing 6 cases in which patients treated with it experienced an increase in suicidal behavior soon after beginning treatment. The Committee on Safety of Medicines (CSM) in the UK blamed suicides on Paxil and came to the conclusion that it shouldn’t be prescribed to patients younger than 18. Given the actions of the CSM and raised public concern, the FDA was forced to reanalyze the data on SSRIs.
The agency conducted a meta-analysis of 372 randomized trials of SSRIs involving nearly 100,000 participants. The results showed a 4% increase in suicidal thinking or behavior in patients treated with SSRIs as opposed to a 2% increase in patients on placebo. Further analysis showed that this increased risk was significant only in children and teens younger than 18; there was no evidence of increased risk in patients older than 24.
In response to this data, in 2004 the FDA issued a black box warning for all SSRIs. The black box warning-the most severe warning bestowed by the FDA-was meant to inform people about the increased risk of suicidal tendencies in teens and children under 18 during initial treatment. In 2007, this warning was extended to patients under 24.
The warning has not been taken lightly, and according to Muir, it had an observable impact on cases of completed suicide in teens. “People got scared and didn’t put their kids on SSRIs so the completed suicide rate actually increased after the FDA warned people about suicidal thoughts associated with antidepressants,” he said.
According to an article in Pharmacy and Therapeutics by Jack Alan McCain, the high suicide rates among kids and young adults between the ages of 10 and 24 started decreasing in 1990 falling from 9.48 to 6.78 per 100,000 persons between 1990 and 2003. Yet, by the end of 2004, the suicide rate had increased by 8% and has largely continued to increase since-according to the Center for Disease Control in 2014 the rate of suicide rate in the 10 to 24 age group was at 26.9 suicides per 100,000 persons. In 2015 suicide was the third leading cause of death in kids 10 to 14 and the second leading cause of death in individuals between 15 and 24.
At this point it’s worth asking, if teenagers stopped taking SSRIs due to the warning, and this caused an increase in completed suicides, does that prove SSRIs are effective for treating even the most severe cases of depression?
It’s hard to look at this evidence and not conclude that SSRIs can help treat depression in teens. But, the relationship between the black box warning and an uptick in suicides might only be correlational. Yes, there seems to be something that ties the two events together but there could also be a myriad of societal, environmental and other factors that caused suicide rates to go up. Increasingly competitive environments in school, the advent of social media and cyberbullying, and an overall decline in play that has accompanied technology like XBoxes and iPads, have all been cited as possible reasons for increases in depression, and in turn, suicide rates among children and teenagers.
Also as Simons, would point out, since the early scare with SSRIs, prescriptions for antidepressants have actually been rising. According to the CDC for example, one in ten Americans aged 12 and over was on an antidepressant in 2008. A rise in antidepressant prescriptions coupled with a rise in suicide rates then complicates the notion that the FDA’s actions are responsible for more suicides.
Ask any psychiatrist and they’ll all tell you the same thing, the only way to prove the efficacy of antidepressants is through controlled experiments, and that’s where the proof is lacking.
Lori Evans, a colleague of Muir’s, also works at the Child Study Center at NYU but unlike Muir her approach to patients is entirely therapeutic. Evans specializes in Cognitive Behavioral Therapy and therefore gets to spend a lot of time with her patients-especially at a diagnostic appointment. At the Child Study Center the diagnostic appointment generally takes around 3 hours and follow ups last about 1 hour each-a lot more than the short appointments that are typical of psychiatrist visits (some of which are as short as 15 minutes). But even with this long time to observe and talk to a teen and their parents Evans still finds it difficult to diagnose depression in her young patients.
According to Evans, when diagnosing an adult, a therapist doesn’t generally need to consult their Diagnostic Statistical Manual (DSM) and tick off symptoms to see if they have depression.
“The impairment in their functioning is so global, and that idea of having their low mood so ubiquitous that it’s clear. With teenagers, I think one of the difficulties for people looking at them is that, depending on the situation, they can look totally fine,” she said.
In her experience teens might be depressed but appear to still be able to experience happiness, for example, they may be feeling low and hopeless overall but still manage to go out to a party on a Friday night, baffling their parents and therapists and making it harder to determine if they are depressed, and if so to what degree.
Of course, there’s also the fact that teenagers are still developing and changing and coming into their own personalities-the stereotype of the moody and emotional teenager doesn’t make diagnosing any easier.
The best way to diagnose depression in a teen is to look at their baseline-how they are normally-and identify how far their behavior has drifted from that baseline.
Evans likes to illustrate this through a preschooler that she’s been treating for a few years in an ADHD study. According to the boy’s mother, he used to be Tigger from Winnie the Pooh, loud, rambunctious, and bouncing off the walls. Tigger was this patient’s baseline, an energetic baseline, but a baseline nonetheless. Given this baseline, when the boy’s mother later called her and said her Tigger had turned into an Eeyore, Evans knew there was a fundamental change.
It’s drastic changes like this that signal the onset of something like depression in a teenager, but again, the changes aren’t always so clear cut.
Another issue with diagnosis is that because it is so difficult to find an adequate diagnosis, and because psychological jargon, and especially the term ‘depressed’ are so commonplace, the actual mood disorder is often over-diagnosed.
“If people actually followed the DSM diagnosis, they might diagnose it less. The problem is, you come in and you say, ‘oh, I’m so depressed, I feel so hopeless’-ok you’re depressed. But wait a minute, there are more criteria in the DSM than that. Do you really meet all the criteria?”
There are two main issues then with diagnosing depression in teens, first, it’s hard to diagnose accurately in the first place. Second, teens who are diagnosed with depression may not actually be depressed. Of course it can be argued that if a teen is going to therapy, they probably require therapy and any therapy would be better than nothing and this is true-but when meds get involved, there is a huge danger in misdiagnosing a mood disorder.
In the words of Evans, “diagnosis is important if it dictates [medical] treatment.”
There are two mood disorders-unipolar depression, or depression in everyday terms, and bipolar depression. Though both affect mood and may cause a person to feel down, bipolar disorder is also characterized by episodes of mania-periods of great excitement, euphoria, delusions and overactivity.
The trajectory of bipolar disorder typically begins with non-specific disorders in childhood such as anxiety, these are later followed by major depressive episodes in early adolescence and then manic episodes.
The two disorders work on different neurotransmitters. Depression is influenced by serotonin, while bipolar disorder is influenced by dopamine. According to the information we have, bipolar disorder is caused by the degeneration of dopamine neurons in the brain, and is treated with antipsychotics that inhibit dopamine neurotransmission. It makes sense then, that SSRIs which act on an entirely different neurotransmitter would be inadequate to treat a disorder that has to do with a person’s dopamine levels.
“SSRIs are cycle frequency increasing medications, in bipolar disorder they are definite no-nos, you stay away from them, the guidelines are you don’t use them, the evidence says they don’t work,” said Muir.
What’s more, treating a bipolar teen with with SSRIs is dangerous. Not only might the teen not improve, her condition would worsen. When SSRIs are used in a bipolar person, they have the potential to destabilize mood, cause rapid cycling between manic and depressive episodes, increase the likelihood of substance abuse and through all of these factors, increase the risk of suicide.
With depression being the main risk factor for suicide and suicide being the third leading cause of death in teens it makes sense that a psychiatrist would use the SSRIs in their toolbox to treat the apparent depression-after all, these drugs have proven to an extent to reduce completion of suicide in unipolar depressed teens. But as we have seen, some teens don’t always respond to antidepressants and do end up completing suicide even while on drugs.
A paper by Stephen Hogg of the University of Cambridge suggests that teen suicides associated with antidepressants may result from improperly diagnosing bipolar teens with depression, and then treating them with SSRIs.
According to Hogg, “It has long been documented that patients with bipolar spectrum disorders have increased lifetime rates of suicide compared with those with unipolar depression” which means that bipolar teens are more suicidal to begin with. Giving them drugs that don’t treat their dopamine deficit and may increase their mania might be the nudge they need to go through with suicide.
The cause of a high rate of teens on SSRIs killing themselves then may not have anything to do with the efficacy of their meds, but rather with the accuracy of their diagnosis.
“It’s not complicated as an illness. You either have an episode of mania or you don’t,” said Muir of diagnosing bipolar disorder.
But as Hogg brings up the case of the depressed teen you’re treating who hasn’t yet had a manic episode. Do you wait and see if it’s going to happen before prescribing an SSRI? Or simply assume your patient is bipolar, prescribe a mood stabilizer, and ignore his depression? If your patient is so severely depressed that they’re contemplating suicide, you can’t really afford either option. That’s why even Hogg who thinks we may be pushing bipolar kids to suicide through misdiagnosis concedes, not treating with SSRIs is not an option.
In a teen presenting with what a depressive episode, that might actually be a step in their development of bipolar disorder, mistreatment with SSRIs might worsen the situation or lead to suicide.
“However, this alone is not sufficient to support a reduction in antidepressant therapy,” he said.
Differentiating between bipolar depression and unipolar depression may be extremely difficult in the absence of a manic episode, as Evans showed even a diagnosis for unipolar depression is elusive-but diagnosis is clearly important. What we should consider then is a way of coming to a proper diagnosis and treatment perhaps not through clinical characteristics but by finding something more concrete like a biomarker that would dictate the best course of action.
“I want you to substitute the word depression with cancer,” that’s what Dr. Helen Mayberg will ask you to do to begin making her case for precision psychiatry.
She then will ask you to think of how we treat cancer. First of all, we do a biopsy to figure out if you even have cancer. Then, we have to identify the type-is it breast? Colon? Bone? Lung? Once we know this and run all the tests we have available to know everything we can about a patient’s cancer, then we choose treatment. We don’t choose just any treatment either, we choose the treatment that will work for that particular type of cancer and that particular case. We don’t just wing it.
Mayberg chooses cancer as a stand in for depression because in her opinion it’s a disease that unlike depression, we take seriously. It’s not that she feels we should be treating depression as more important than cancer, it’s that we should approach both diseases with equal rigor and just like we use science and technology to determine the best treatment for a particular case of cancer, we should be doing the same for depression.
“The assumption that everybody will get better on average with any treatment is just not the way that anybody can think about anything now…You need to be characterizing who should or shouldn’t get a treatment,” said Mayberg.
According to Mayberg one of the biggest issues with the way we treat depression is that we largely approach it through trial and error. Depressed patients often start with an SSRI, when that doesn’t work they switch to another, and then another until something sticks. Maybe at some point they start therapy and finally that works. Or maybe they started with therapy and wasted hundred of dollars on something that never made them feel any better. Wherever they start the odds that a depressed patient will get better on their first treatment are pretty low.
Another way we approach treatment for depression is through patient choice which Mayberg has shown through her research, does little to improve a patient’s chances at remitting. The idea that patient preference will affect their response is “magical thinking” after all, you wouldn’t argue with your cardiologist about how he should treat you-you would just do what works.
With depression, as with any other disease, it’s imperative to treat fast and accurately to improve a patient’s quality of life. Failed treatments aren’t just struggles for psychiatrists and therapists to throw their arms up at in frustration-they’re things that have important implications for patient’s lives.
“What’s the financial, and social, and disability burden of 6 months not being well? Considerable if you work or go to school or have a family. A you might kill yourself, B might lose your job, C you’re not very efficient and you feel terrible,” she said.
Mayberg’s suggestion then is that we approach the treatment of depression like we do cancer, and basically any other disease, through precise treatments that we know are best tailored to a particular patient. This approach to mental health is called “precision psychiatry.”
The brain is extremely plastic and is constantly trying to get to a normal state when it is undergoing stress or depression. The thing is, different brains try to fix themselves in different ways and so the treatments that we put depressed patients through can either help the brain get over that ledge of depression or work against it and make it harder to get to a base state.
“The question is, what’s different about a person who gets better on therapy than a person who gets better on drugs. Are they interchangeable? And it turns out, it doesn’t seem that they are,” she said.
What Mayberg has focused her work on is identifying these different brain types to create subtypes of depression and identify which brain works best with what therapy. She has used fMRI to look at the subcallosal cingulate cortex (SCC)-an area of the brain that has been implicated in depression-and the areas around it to see what brain patterns correspond to treatment responders.
Through her work Mayberg has identified therapy type brains and drug type brains-that is brains that have a particular communication patterns that either respond well to cognitive behavioral therapy or antidepressants.
To find these biomarkers Mayberg took brain scans of depressed patients who had never been treated before. After imaging their brains, patients were randomized to receive an SSRI, an SNRI (selective norepinephrine reuptake inhibitor-another class of antidepressants), or cognitive behavioral therapy. Once treatment had ended, researchers assessed the patient’s response to their treatment and looked back to see if they could group responders to certain treatments according to similar brain patterns, it turns out they could.
The results showed that if a patient had regions in the SCC that were exhibiting positive functional connectivity they were more likely to do well on CBT and poorly on medication. On the other hand, if functional connectivity in this area was poor or negative, the patient did well on medication but poorly on CBT.
To Mayberg the implications for treatments we have are clear: there are subtypes of people for whom a drug will never provide a cure and others for whom a drug is the only way to alleviate their depression.
Of course she isn’t suggesting that all medical professionals need to order an fMRI before they decide how to treat their patients just yet-these results do still need to be replicated, and fMRIs are very expensive. She does however think that her work has important implications for treatment, namely that people do seem to have different brain types and that treatment should be approached with this idea in mind. To Mayberg there is a simple translation from the brain imaging she does in her lab to the real world, if the first treatment a patient tries doesn’t work, they should be triaged into the other camp.
It’s a simple concept from a medical and logistical perspective, if one type of treatment doesn’t work, it’s probably because it’s not right for that patient and the optimal thing would be to try a different approach rather than a slightly different form of the same treatment.
It even makes sense from the perspective of insurance companies which are often the ones that actually decided what treatments patients do and don’t have access to. If a patient isn’t getting better on Prozac, it makes more economic sense to try something new and get them into therapy rather than keep pouring money into more drug prescriptions.
It’s easy to understand why doctors often prescribe different pills as opposed to a different treatment when the first dose of Prozac doesn’t work-they’re cheap, seem faster, and might have less social stigma than other cures . But Mayberg’s work with brain types shows that there is an argument for treating depression like any other disease and creating precise treatments.
Precision psychiatry has a long way to go but the benefits of being able to treat a depressed teen with an approach that is going to work on the first try are undeniable. Being able to tell the difference between a brain that will respond to pills and one that will do well with therapy seems like the best possible test to take a teen from the brink of suicide to a full adult life. In the words of a hopeful Mayberg, “the state of the brain determines your behaviour. So the state of the brain is determining how you should be treated. Lets, lets follow that lead.”