Posts tagged: antidepressant

Sixty Minutes of Placebo

Recently, the news magazine 60 Minutes offered a piece on the role of placebos in the treatment of depression.  If held to the usual standards of broadcast journalism, the piece would not be particularly disturbing.  The 60 Minutes news magazine, however, has a strong track record of breaking news stories in an accurate and reliable fashion.  Historically, 60 Minutes held a higher standard for the subject matter examined, and the depth of its reportage.  Lesley Stahl’s piece on placebos was a break in this chain.  It tended to confuse the issue, rather than draw a conclusion from the evidence.  The confusion was not limited to the role of placebos, but the role of antidepressants in general.

Lesley Stahl’s piece made the assertion that antidepressant effectiveness is largely due to the placebo effect.  This is not news.  The fact that drug companies only select those studies that are favorable to their drug, suppressing the unfavorable studies, is also not news.  A number of detailed and accurate books have been published on this exact topic-even a critique by a former director of the American Medical Association.  It may have been news if Mrs. Stahl focused on the consequences of suppressing unfavorable studies.  Instead, Mrs. Stahl attempted to appear impartial by berating the Harvard professor whose research has reinforced the role of the placebo.  It may have been news if Mrs. Stahl found that the professor’s research was flawed.  She cast doubt on his conclusions without ever achieving some conclusion of her own.  She appealed to psychiatrists, paid by drug companies, as experts to evaluate the research of an unbiased academic.  At no time in the piece did Mrs. Stahl refer to the professor by his correct title, though she unfailingly referred to drug company psychiatrists by their professional titles.  The end result was to cast doubt on both placebos and antidepressants.

The first fact to consider is that most competent psychiatrists are just as concerned with side-effects as the intended effect.  A patient who cannot sleep is given a sedating antidepressant over one that is activating.  A patient who sleeps too much and can’t wake in the morning is prescribed an activating antidepressant.  Patients who are overweight are prescribed antidepressants that cause minimal weight gain, while those who have lost their appetite and are losing weight are given antidepressants that increase appetite.  The side-effect of medication is often as important in the treatment of depression as the main intended effect.  The only difference between a medication’s side-effect and main effect is the intention of the humans that formulate the drug.  The human body does not know the difference between side and main effects of medications.  This very important feature of antidepressant medication treatment was never mentioned in Mrs. Stahl’s report.

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The third and last fact to consider is that placebos have been researched for over fifty years.  This is far from being newsworthy.  It is like breaking news on the value of soap and water.  The brain’s response to placebos and antidepressant drugs is nearly identical.  Using brain scans that take snapshots of brain metabolism and activation (PET), researchers have discovered that placebos cause a similar increase in brain activation (glucose uptake) as antidepressant medication.  Placebo treatment is not known to cause an increase in brain neurogensis, but this appears to be an artifact of scant research, rather than from actually being disproved.  Well-controlled studies may yet reveal that placebos cause neurogensis, but there is little economic motivation to perform this study.  If Mrs. Stahl questioned why drug companies decline to research placebos, that may have been newsworthy as well.

In summary, Lesley Stahl danced around the relevant issues regarding antidepressant medications.  Perhaps she was unaware that the side-effects of drugs may be therapeutic, that SSRIs potentiate neurogenesis, and that both placebos and drugs affect glucose metabolism in a similar fashion.  Mrs. Stahl fell short of asking relevant questions; for example, should antidepressant medication be used primarily for its side effect(s), should physicians continue to recommend drug treatment over psychotherapy, and should drug companies market psychotherapy in combination with placebos or antidepressants?  Any one of these questions may have received an answer that could have changed the future of depression treatment.  Important aspects of depression treatment were ignored, while well-proven old information was touted as breaking news.  Lesley Stahl’s piece failed to arrive at a conclusion, let alone a call to action.  It is unfortunate that the net effect of Mrs. Stahl’s piece will be to further confuse the issues surrounding the current treatment of clinical depression.  It was not 60 Minutes‘ finest hour; certainly not their finest fifteen minutes.

Genetically Modified Depression

Most people know that DNA contains the data that programs all living things.  What is less known is how the shape of the DNA affects the ultimate expression of proteins.  The mechanisms that regulate if and when proteins are expressed by the DNA template is a very hot topic of research.  Not only the packing but the chemical markers attached to the DNA appear to be important in gene expression or inhibition.  Vast areas of DNA that had been labelled as “junk” are increasingly found to be important in the regulation of protein production.  Only a few percent of a person’s DNA is actually a blueprint for protein production.  The remainder is an intricate network of feedback and feed forward mechanisms that start and stop protein production.  Tightly packed DNA tends to decrease protein transcription, and relaxed DNA strands increases the chance a gene will be expressed.  Two groups of chemical markers have been discovered that regulate the DNA packaging, and hence the ultimate expression of any particular gene.  So, one may ask, what has this to do with mental health?

The chemical groups that regulate gene expression are critically important to the understanding of addiction and depression.  Within an hour of injecting mice with cocaine, over one hundred genes become activated.  If cocaine is used everyday, particular genes are actually inhibited from expressing proteins.  Prolonged use may render some genes over-activated for weeks and even months, whereas others become chronically inhibited.  The ingestion of this one chemical causes profound genetic alterations in the brain’s reward centers that may persist long after the drug is discontinued.  Many genes remain highly sensitized to the effects of cocaine for several weeks after the mouse was last injected.  The brain is ready and waiting for the next dose of cocaine.  The cocaine causes the epigentic chemicals to loosen the strands of DNA; priming them to be activated.

In depression, the the epigenetic influence on DNA is nearly opposite to that of cocaine abuse.  Depression appears to be the consequence of repressed gene activation in the reward centers of the brain.  Environments that are abusive will tend to make the DNA strands tightly bound; decreasing gene activation.  For example, a mouse that is not able to escape the domination of a more powerful mouse will display decreased activation in twelve hundred genes!  Depression appears to inhibit the activation of DNA in the reward centers that allow an animal to feel good.  Just as many humans are resistant to depression, about one third of the mice in the bully experiment did not manifest symptoms of depression.  The resilient group of mice did not develop the the inhibited gene expression that infected the larger depressed group.  This sizable group of genes in the reward center of higher animals is implicated in the treatment effectiveness of tricyclic antidepressants.  Some antidepressants may actually boost the brain’s natural mechanism to confer resilience.
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Addiction and depression are not the only psychological manifestations of epigenetic modulation.  As described by Eric Nestler in Scientific American (2011), epigenetic “modifications can promote behavioral changes that last a lifetime.”  Maternal rat behavior is partially or completely modulated by epigenetics, and this has lasting effects on the offspring.  The memory area of the mother’s brain is inhibited, and this epigenetic reduction increases the stress response of the mother over their lifetime.  Anxious and fearful mothers produce a change in the epigenetic regulation of their pups, and this effect will reverberate down the generations.  The behavior of the mother will alter gene expression in their children, and their children’s children.

As with so many discoveries in neuroscience, what works in a mouse may not generalize to a human.  It is likely that humans have the same epigenetic marks that influence gene expression, but it may deviate from what is observed in mice and rats.  Additionally, the complexity of the human brain often makes it difficult to reduce an observation to a few simple rules of organization.  It is nearly impossible to tease out the influence of genetic inheritance from the effects of the environment.  The relative influence of environment versus heredity has been hotly debated for decades, if not centuries.  If this research proves valid in humans, it renders the nature versus nurture debate practically moot.  Increasingly it appears that the environment has a profound and lasting effect on gene expression.  The role of gene expression can no longer be considered in isolation, as if it is the last word in the life story of the organism.  Perhaps the duality of genes and environment will have the same fate as that of the mind and body.  One can only be understood in relation to the other.