Reflection on Depression

Antidepressant drug trials: Is the research reliable? (Or how to research things we don't understand!)

My impression from following open clinical trials (in order to participate) is that the bulk of antidepressant research is conducted on outpatient subjects -- people who can drag themselves to a research facility, sign up for a study, go through an intake process, and risk a 50% chance of placebo. Because few severely depressed patients can do all of that, I suspect that severe depression is underrepresented in the subject pools. No wonder, then, that the trials show low efficacy; it's well known that the drugs work best (or only work) in cases of severe depression.

The last time I was acutely depressed I called my doctor the day after Christmas to schedule an emergency appointment (it took everything I had not to call her on Christmas). If I hadn't been able to see her I would have gone to the nearest ER. There is no way that I would have had the wherewithal, the ability, or the spectacularly bad judgment to participate in a study instead of seeking immediate treatment.

Severe depression is also underrepresented in pools of research subjects because there are ethical proscriptions against allowing obviously suicidal patients to participate in studies. Those patients are referred to a hospital instead. In other words, patients have to be reasonably well in order to participate. Moreover, patients with delusions or hallucinations are often disqualified from participating in research on depression unless the study is looking specifically at psychotic depression. 

These limitations may explain why antidepressant medications show more clinical benefit than the research predicts. After all, in real-life practice doctors treat patients from across the severity spectrum, whether or not they would qualify for a drug trial.

A national paper publishes the OTHER side of the antidepressant debate

Last weekend an article titled "In Defense of Antidepressants" appeared in the New York Times.

It's refreshing to finally see a newspaper provide balanced coverage of the antidepressant debate!

The author, a psychiatrist at Brown University, examines the controversial study I discussed in my last post -- a study that many news organizations sensationalized and oversimplified earlier this year. He also describes the limitations of antidepressant research generally, including the inclusion of non-depressed patients in studies, the conflation of different types of depression, and the danger of ascribing too much authority to single trials. 

Are antidepressants better than placebo? A podcast from Stanford Medical School

Below is a link to a Stanford Medical School podcast of an interview with Robert DeRubeis, the lead investigator of a meta-analysis which revealed that antidepressants are no better than placebo in many cases of mild, moderate, and even severe depression (essentially, in all but the most severe cases of depression). DeRubeis discusses media coverage of the study, the reactions of primary care physicians, and his interpretation of the study's results.

See here for the podcast. 

The results of the study align with my own anecdotal experience. During my most acute depressions--those times when I truly felt like I was losing my mind--the illness responded rapidly and robustly to medication. (These are the two episodes when my HAM-D score was over 30). However, the drugs have done little to treat my milder, residual depression (even if they are still important as a maintenance measure to stave off relapse).

I'm glad that someone is parsing our coarse classification of depression into more exacting categories and examining the effectiveness of medications for those different tranches of the disorder. Experience and common sense suggest that the disorder is heterogeneous and that treatments need to progress beyond a "one size fits all" approach. Patients should be channeling resources to the most effective evidence-based therapies first, not prolonging their pain and wasting resources by starting with unsupported treatments.

I wasn't surprised by the study but I disliked much of its media coverage. (The pic above is from an egregiously irresponsible Newsweek article:  Why Antidepressants are No Better Than Placebo). As DeRubeis points out--and as many media outlets failed to mention (or bury as a caveat several paragraphs in)--a mountain of evidence indicates that antidepressants are effective at treating the most severe depressions. His study, however, examined treatment of a wide range of severities.

Antidepressants and mood stabilizers had an enormous effect on my worst episodes and probably saved my life. That doesn't mean they are the right solution for many (even most) patients. 

Treat smarter, not harder

Last week I read about a couple who lost their daughter to suicide after she "stuck with a single therapeutic mode and her prescribed medications even though the combination seemed to just make her worse". Her conscientious adherence to a single therapeutic regime even when it wasn't working reminded me of the importance of changing or supplementing treatments when one isn't working.

In my experience, patients are too hesitant to change treatments mid-course if progress stalls. There's a misconception that recovery requires holding fast to any treatment prescribed, and it's exacerbated by the tendency of psychiatric patients to blame themselves for not getting better because they aren't "trying" hard enough. 

Effective treatment does require time, patience, and persistence (often, effects aren't seen for a couple of weeks), but sticking with an ineffective treatment indefinitely diverts resources from alternatives that may work better. In my case, I stuck with (and my parents paid for) a vitamin and nutrition program long past the point at which more serious medical intervention was necessary.

Also, you may hit upon a good therapy but at the wrong time. That was the case when I first tried cognitive behavior therapy (CBT). I was so depressed--and my brain was so out of whack--that I couldn't even begin to pull out of the depression without biological intervention. Trying CBT before medication was discouraging. It made me feel like I was "failing" at therapy, and my lack of progress made me worried that I would never get better, regardless of treatment.

Finally, some treatments can exacerbate depression. SSRI medications that induce suicidal thoughts in a small percentage of patients are the most obvious example. When this is the case, diligence can be deadly. It sounds like common sense, but if your treatment is making you worse, you should STOP that treatment. Every brain is different. Don't assume that a medication is right for you just because you know another patient who experienced its benefits.  

It's true that certain treatments are supposed to be uncomfortable. The standard treatment for phobias, "exposure therapy," is a perfect example of a treatment that involves purposely leaving your comfort zone. Moreover, opening up to a therapist or adjusting to some medications may be difficult at first. However, if the treatment is ineffective, then you need to take action. An unwavering commitment to getting well is necessary, not an unwavering commitment to one treatment modality, one doctor, or one therapist. 

Most important, do NOT let failure at one mode of treatment convince you that you won't get better. Sometimes people who don't response AT ALL to medications respond well to therapy, and vice versa. Also, researchers are developing new therapies every day. Deep brain stimulation, transcranial magnetic stimulation, and vagus nerve stimulation, are all examples. The odds are on your side--most people eventually find a treatment that works. 

 

Alternatives to medication and ECT

Although medication and ECT are the primary medical interventions for severe depression, a number of more experimental options are becoming available. In this column about treatment resistant depression a doctor advises a reader to look at transcranial magentic stimulation (TMS), vagus nerve stimulation, and deep brain stimulation (which is where doctors implant electrodes directly into the brain).

Although some of these treatments sound extreme (DBS requires brain surgery), they may actually be safer and more effective options than staying on medication for a lifetime. Moreover, TMS and DBS seem to have very few side-effects. No weight gain, mental fogginess, or drug interactions to worry about!

I asked my doctor about TMS recently but learned that it cost over $200 a session and isn't yet covered by insurance. That makes it over $4,000 for the standard 20-session treatment. One 20-course treatment is still cheaper than a lifetime of meds, but it's my understanding that patients must continue to undergo treatment periodically. At $4,000 a pop, that could add up quickly!

I also looked into DBS but it is still in clinical trials. However, approval should be realtively fast because it has been approved to treat movement disorders like Parkinson's for nearly 20 years (thus its safety record is well-established).

Depression subtypes: reactive, atypical, melancholic, psychotic

Subtyping depression is an overlooked task in mental health research. After all, depression is most likely an umbrella term for a number of different disorders, some more serious than others. I believe that much of the vitriol infecting the debate over whether depression is "biological" or "psychological" arises from this underlying variety in etiology. Unfortunately, the American classification system codified in the DSM categorizes depression along a single spectrum from mild to severe.  

Not everyone finds this spectrum adequate. For years, researchers have used the term "endogenous depression" to refer to apparently biologically-based depressions (as opposed to reactive depressions that occur after a psychological stressor). Moreover, many psychologists have long recognized a so-called "atypical" depression, which is characterized by reverse vegetative symptoms (e.g. weight gain and hypersomnia instead of weight loss and insomnia), while "melancholic" depression is a severe manifestation of the traditional syndrome.

Outside the US, clinicians are even more specific. In Britain, the Black Dog Institute has constructed its own classification system which posits three types of depression. From the website: 

There are two distinct categories of essentially biological conditions (melancholic and psychotic depression) which have identifiable defining features, and a residual group of quite varying conditions (non-melancholic depression).  This residual group is therefore associated with varying presentations reflecting the contribution of life event stressors and personality style.

In all three subtypes there is a mood disorder component.  The key features include a depressed mood, decline in self esteem, self-criticism, the mood state is present for at least 2 weeks and causes social impairment.  The key feature which defines melancholic depression is observable psychomotor disturbance (PMD) – e.g. retardation and/or agitation together with a cognitive processing difficulty.  In psychotic depression, the PMD is generally more severe and combined with psychotic features such as delusions, hallucinations and/or over-valued ideas.

I experienced melancholic depression, as well (I suppose) as the more common reactive depressions. When severely depressed with melancholic symptoms, I experienced weight loss (in my case more than 15% of my body weight in a couple of weeks), extreme psycomotor retardation (I spent most of the day in bed), and extreme guilt. I also experienced strange thoughts. At one point I was convinced, among other things, that I was such a bad person I belonged in federal prison (why federal prison and not state prison? I don't know. Logic doesn't necessarily apply to delusional thinking).

I hesitate to say I had a psychotic depression because my thoughts were not entirely delusional (my guilt was based on real incidents, it was just wildly out of proportion). Also, I retained enough awareness to know that my thoughts would seem strange or untrue to others. For that reason, I kept them mostly to myself (perhaps hiding the severity of my condition). At a certain point, however, those strange thoughts became so constant, intrusive, and compelling that I sought help from a clinician who thought I must have OCD.

I don't think I had OCD, but rather a severe case of melancholic depression. Because "depression" has become such a watered down term, some patients (and clinicians) forget that severe melancholic depression can cause halucinations or delusional thinking that mirror schizophrenia, and intrusive thoughts that mimic OCD. Because we've failed to subtype depression into parsimonious categories, our understanding of it is as jumbled as the diagnostic category. 

This confusion hinders both research and treatment. For instance, since melancholic depression is less common than reactive depression, treatments that might work on melancholic depression could fail to reach statistical significance in an experiment that doesn't exclude patients with reactive depression from the study group. It's a bit like concluding that chemo doesn't work for lung cancer after testing it on a group of patients who all have a cough. 

I hope that one day we develop a more nuanced model of depression. For we can only really begin to research and understand a condition once we've identified it. Unfortunately, pharmaceutical companies have little incentive to promote a more robust classification system; subtyping depression would only fracture the currently enormous market for their drugs. Also, reactive depression is both the largest category of depression (and thus, the largest market for drug makers) and also the category that may be least likely to respond to antidepressants. In other words, pharmaceutical companies have every incentive to obscure this difference, subsuming it into the more biologically-based cases that respond well to medication.

How do we fund research that better identifies these nuances? I suspect it will take scientists who are willing to go out on a limb, and funding from groups like the NIH that are willing to back studies which could potentially reduce the size of the antidepressant market.

One thing's for sure--we're at the very beginning of our understanding and we don't need someone obscuring the way forward.

Another possible breakthrough - new molecular approach to treating depression

Earlier this week I discussed how scientists may have discovered a way to make the administration of SSRIs safer. Today, word of a different breakthrough is spreading--researchers have identified a molecule that may take antidepressants beyond the current SSRI paradigm. 

See:  New molecular approach to treating depression

As the article notes, little has changed in depression treatment over the past thirty years since the introduction of SSRIs. While the number of antidepressant brands has proliferated, few truly novel drug agents have been developed.

A new understanding of a molecule called macrophage migration inhibitory factor (MIF) may change that. In the study, researchers discovered that the absence of MIF in the brain of rats produces marked anxiety. It turns out that MIF may be key to neurogenesis (new neuron generation) during adulthood, a process that slows down during prolonged periods of depression and anxiety (many antidepressants increase neurogenesis).

It will be interesting to see where this leads. Just as the development of SSRIs transformed the treatment of depression thirty years ago by offering a more appealing alternative than MAOIs and trycyclic antidepressants, the discovery of MIF's role in reducing anxiety could lead to the next wave of chemical innovation.

Identifying adverse reactions to SSRIs -- new scientific breakthrough

Researchers have made a breakthrough in identifying which patients will experience suicidal thoughts as a side-effect of SSRIs. They've discovered that imaging reveals telling patterns of brain activity in these patients. This could be a BIG step in making antidepressants safer.

SSRIs are widely prescribed because of their relative safety over older antidepressants. However, a small subset of patients (between 5 and 14%) experience an increase in suicidal thoughts while taking them. Now, researchers report that QEEG imaging reveals a distinct pattern of brain activity in patients who experience this side effect. Apparently, certain regions of the brain display a sharp decrease in activity during the first 48 hours that patients who will experience the side effect are taking an SSRI.

A method of identifying patients who are experiencing (or will experience) an adverse reaction to antidepressants is critical--especially in the case of children and adolescents who are at a heightened risk for this reaction. As I've discussed previously, early-onset depression should be treated aggressively because of its potentially serious developmental consequences. This means that parents should remain open to the idea of treating their children with medication.

After black box warnings were added to antidepressants in 2004, the number of parents forgoing medication for their children increased significantly. Following the warnings, the teen suicide rate spiked by 20%, possibly because too many doctors and parents were scared off. Now there's hope that we can have the best of both worlds--adequate disclosure of the risks as well as the ability to try the antidepressants in children and quickly terminate the treatment if it's causing an adverse reaction. Hopefully this research can be transferred to a clinical application soon!

Brain imaging to identify suicidal thoughts in patients taking SSRIs

GABA dysfunction in severe depression

After my own experience with extreme depressive anxiety and obsessive thinking, I am not surprised to see a new study in Biological Psychiatry suggesting that patients with severe depression display low levels of GABA--an inhibitory neurotransmitter that "applies the brakes" to excess brain activity by calming overactive neurons. 

Sedative drugs like benzodiazepines, which are used to treat anxiety, seizures, and sleep disorders, enhance GABA efficiency. Although a number of antidepressants already work on neurotransmitters like serotonin, dopamine, and norepinephrine, a GABA-centered therapy could be a new approach to treating depression.  

Study - The role of GABA in severe depression 

In my case, benzodiazepines were used off-label to treat my extreme anxiety and discomfort at the worst of my depression. I can't begin to describe how helpful these drugs were in allowing me to function during this period. At its worst, depression paralyzed my mind with obsessive thinking about past transgressions. Although I was aware that my level of guilt and obsession was irrational, I was unable to steer my thoughts in any other direction. The intrusive thoughts felt like a strong rip tide sweeping me toward insanity, and the harder I tried to swim against the current the worse things got. At my lowest, I could barely hold down a conversation, had stopped eating, and was in a constant state of discomfort -- I would lie in bed for hours at a time unable to go more than a few seconds without the thoughts. When I eventually got up, I was unable to do anything but pace around the house. There was no activity that was comfortable--not lying down, not pacing, not talking. I would switch from one to another only to find that the pain plagued me regardless of what I was doing.

Benzodiazepines were a godsend in my situation. They didn't restore control over my intrusive thoughts -- it wasn't until months later that I found Lamictal and finally regained most of that control -- but they turned down the volume long enough for me to be moderately functional. I was able to eat again, avoid taking time off from school, and engage with others enough to feel like I hadn't completely dropped out of everyone's life. Benzodiazepines bridged the gap in time between the onset of acute symptoms and finding an effective, long-lasting treatment.

Although benzos can be dangerously addictive, when used under the care of a professional they can go a long way toward restoring function in patients whose lives have been turned upside down. I imagine they are a bit like morphine for the mind -- not good for you, but necessary in certain situations to make life livable. 

In my case they took a huge burden off my family as well. Before starting the drug, we almost had to cancel a long-planned vacation to Hawaii because I was so sick. After my first few doses I felt confident I could make the trip -- even if it wasn't under ideal circumstances. The change in my ability to function was enormous -- it was like the difference between being in a wheelchair and walking with a limp. And since I was more functional, I was also able to take responsibility for my own healthcare rather than burdening my family with arranging appointments and constantly monitoring me.