BETHESDA, MD—Mood disorders remain some of the most debilitating diseases afflicting the nation. Major depression is the leading cause of disability in the world, topping even heart disease. Bipolar disorder ranks at number 8. And yet, there are few treatments available compared to other ailments, and mood disorders are not always treated as the serious threat they can be. “The major mental disorders tend to strike people when they’re adolescents and young adults, and they tend to be chronic and recurrent,” explained Kathleen Merikangas, PhD, chief of the genetic epidemiology research branch at the National Institute of Mental Health. “If we look across the lifespan, people lose so much time from depression, not only from themselves, but from their families, lives and societies. They are chronic life-long disorders.”

Heavy Impact of Depression

Depression can become such a crippling factor in someone’s emotional and social life because it strikes at such a crucial time, explained Dr Merikangas, who laid out the national impact of mood disorders at a symposium on the NIH campus here last month. Because depression usually presents during adolescence and young adulthood, it has a profound effect on a person at a point when they are going through major life changes. “Depression strikes at that time of life. They get depressed. They miss school; they leave school; they can’t function; they can’t choose careers. It has a major effect on people’s education and occupational attainment, which has a lifetime cascade of people being unable to function or accomplish the major tasks of life,” Dr Merikangas noted.

According to NIH data, nearly $45 billion in lost productivity can be attributed to depressive disorders. Much of that number is attributable to the reduced performance of people coming to work when they are suffering from depression, rather than from absenteeism. “On average, people with major depression, lose 10-15 days per year when they don’t come to work, and when they do, they have diminished capacity to work effectively,” Dr Merikangas explained. “Depression also has dramatic impact on people’s roll functioning as spouses, family members [and parents].”

NIH has been striving to create a more comprehensive picture of how mood disorders manifest, and what the national patient population actually looks like. In 1990, NIH sampled 5,000 people with its National Comorbidity Survey, the first study to estimate the prevalence of mental disorders. In 2000, they conducted a similar survey that followed up with the original sample, as well as surveying new samples, such as adolescent demographics. These surveys showed that depression tends to occur in early adult life, and the prevalence rates decrease with increasing age.

It was also revealed that females have a much higher risk for depression across their life span. However, “it does not appear they’re more genetically predisposed to develop depression.” According to the study, other risk factors include family history of mental illness, being divorced rather than being married, chronic or acute stress, and a prior history of mental illness or a substance use disorder. While none of those factors were shown as causal, they did increase the likelihood of someone experiencing serious depression.

Future Data Gathering

Population-based surveys are providing mounting evidence that there is substantial overlap of mood disorders not only with substance abuse, but also with neurological disorders, diabetes and cardiovascular diseases. However, much of that data has come from patients seeking help within clinics. “Comorbidity is what leads people to seek treatment. So when we go to a treatment setting, we’re more likely to see somebody who has a number of mental [and physical] disorders,” Dr Merikangas explained. “We’re now moving into general population and seeing to what extent these patterns exist in the general population and not just in clinics.” Currently, NIMH is looking at families in the community to examine the frequency with which patterns of comorbidity occur. The results of these studies would have significant implications for treatment in the sphere of mental health, and also for cardiovascular conditions, neurological conditions and other diseases that prove to have a pattern of comorbidity with depression.

NIH epidemiologists are also looking beyond our shores to examine the global pattern of depression using the National Comorbidity Survey as a template. “Most recently we’ve applied these studies in Iraq and countries that have sectarian violence so we can understand the impact on the mental health and the functioning of people in those countries and compare it to [countries] that are relatively stable,” Dr Merikangas explained. The preliminary results of these surveys show that the United States has the highest rate of mood disorders, with Nigeria ranking the lowest. The median rate is about 12%.

Limitations of Current Treatment

Earlier this decade NIMH researchers decided to take an objective and thorough look at how well the commonly prescribed antidepressants, antipsychotics and mood stabilizers worked on patients suffering from major depression and bipolar disorder. While over 30 such medications were being prescribed to patients, little was known about their effectiveness, outside of initial clinical trials.

As a result, NIMH conducted the STAR-D trial for major depression and STEP-BD trial for bipolar disorder. In each, patients began with the most common preliminary treatment (Saris in the case of depression) and, if they failed to respond or had an adverse event, were moved to the next step of treatment.

The data, released around 2006, showed that 33% of patients achieved remission—the virtual absence of depressive symptoms. Data also showed that in each trial there was a decrease in remission rates as the patients went from one intervention to another. By the time patients in the STAR D trial reached Level 4 (a combination of Effexor and Remeron, a common antidepressant combination therapy), the effectiveness rate had dropped to 12%. Dr Carlos Zarate, chief of the mood disorders research unit at NIMH, explained that, “it frequently takes at least two trials or six months for half of the people to achieve remission. And we have a big problem right there.” Results were comparable for both depression and bipolar disorder.

Another problem with current treatment options is the lag time in effectiveness. It can take weeks, if not months, before current medications start working. Dr Zarate considers this a serious problem, especially when suicidal ideation is a factor. “This is a medical emergency and requires, in my opinion, immediate treatment,” he declared. Data from 1992 through 2001 shows an increase of 47% in patients being treated for suicide attempts at emergency departments. This percentage does not include the high number of suicide attempts in psychiatric hospital units. “One third of those have been between 15 minute checks. Which means I ask them whether they are feeling all right, and they say they are. And then I return 15 minutes later and they have attempted to harm themselves or kill themselves,” Dr Zarate explained. A rapidly effective intervention that is commensurate with the urgency of a psychiatric emergency would be invaluable.

Ketamine as Fast-Acting Solution

Dr Zarate and NIMH researchers are currently investigating ketamine—a drug that blocks the brain receptor NMDA—as a possible fast-acting antidepressant. Previous research using ketamine for patients with treatment-resistant major depression have seen “robust, rapid, and relatively sustained antidepressant effects,” Dr Zarate said. “We were achieving comparable response rates on day 1 as opposed to 8 weeks,” he said. After one infusion, an average of 35% of the study participants met response criteria by the end of the week. The STAR-D study showed an average between 31% and 35% after 10 to 14 weeks. Doctor Zarate was also very optimistic about the success ketamine had in treating suicidal ideation. “We can see a dramatic improvement in virtually wiping out suicidal ideation within 40 minutes [in] people who have shown suicidal ideation for up to 10 days. These are people with continuous sustained suicidal ideation.”

Another study on ketamine as a treatment for bipolar disorder had comparable results to the depression study. As opposed to other FDA approved treatments that can take up to 4 weeks to reach therapeutic effectiveness, ketamine begins to work within 40 minutes. Currently, Dr Zarate is engaging in further research examining the mechanism of ketamine’s interaction, and the development of surrogate endpoints to help future drug studies.

Dr Merikangas noted that the extensive comorbidity of mental illnesses with drug and alcohol abuse makes pharmaceutical testing on those seeking treatment problematic. This pattern hinders the testing and release of new therapies, such as ketamine into the general population.

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