Types of Depression
Symptoms of Depression
"Depression Risk Gene"
Role of Chronic Stress
Genetic Interactions in Depression
Changes in Brain Tissue in Depression
Brain Circuitry Increasses Vulnerability to Depression
Genetic Change May Target More Effectve Therapies
Maternal  Care Affects Behavior
Predicting Suicidal Thinking in Teens
Premature Birth Risk with SSRI's
Anxiety and Depression Complications
STAR*D Trial Results
Depression Relapse Less Among Teens with Psychotherapy





Depression: Recent Trends in Research

Course Objectives:

1. Describe the current rate of depression and apply it to "role disability."

2. Describe "optimistic bias" and explain why it is important to predicting outcome in depression research.

3. Describe how specific changes in brain tissues can be linked to the severity of a person's existing depression.



Depression: A Treatable Illness

Depression is a serious medical condition that involves the body, mood, and thoughts. It affects the way a person eats and sleeps, the way one feels about oneself, and the way one thinks about things. A depressive disorder is not the same as a passing blue mood. It is not a sign of personal weakness or a condition that can be willed or wished away. People with a depressive illness cannot merely "pull themselves together" and get better. Without treatment, symptoms can last for weeks, months, or years. Appropriate treatment, however, can help most people who have depression.

Types of Depression

Depression comes in different forms, just as is the case with other illnesses such as heart disease. The three main depressive disorders are: major depressive disorder, dysthymic disorder, and bipolar disorder.

Major depression (or major depressive disorder) is manifested by a combination of symptoms (see symptom list below) that interfere with the ability to work, study, sleep, eat, and enjoy once pleasurable activities. A major depressive episode may occur only once, but it is more common for several episodes to occur in a lifetime. Chronic major depression may require a person to continue treatment indefinitely.

A less severe type of depression, dysthymia (or dysthymic disorder), involves long-lasting symptoms that do not seriously disable, but keep one from functioning well or feeling good. Many people with dysthymia also experience major depressive episodes during their lives.

Another type of depressive illness is bipolar disorder (or manic-depressive illness). Bipolar disorder is characterized by cycling mood changes: severe highs (mania) and lows (depression), often with periods of normal mood in between. When in the depressed cycle, an individual can have any or all of the symptoms of depression. When in the manic cycle, the person may be overactive, over-talkative, and have a great deal of energy. Mania often affects thinking, judgment, and social behavior in ways that cause serious problems and embarrassment. For example, an individual in a manic phase may feel elated and full of grand schemes that might range from unwise business decisions to romantic sprees.

Symptoms of Depression

Not everyone with a depressive disorder experiences every symptom. The number and severity of symptoms may vary among individuals and also over time. In addition, men and women may experience depression differently. Symptoms of depression include:

  • Persistent sad, anxious, or "empty" mood
  • Feelings of hopelessness, pessimism
  • Feelings of guilt, worthlessness, helplessness
  • Loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex
  • Decreased energy, fatigue, being "slowed down"
  • Difficulty concentrating, remembering, making decisions
  • Trouble sleeping, early-morning awakening, or oversleeping
  • Appetite and/or weight changes
  • Thoughts of death or suicide, or suicide attempts
  • Restlessness, irritability
  • Persistent physical symptoms, such as headaches, digestive disorders, and chronic pain, that do not respond to routine treatment

Some Facts About Depression

  • Depressive disorders are common: they affect an estimated 9.5 percent of adult Americans in a given year, or about 20.9 million people.
  • The median age of onset for mood disorders is 30 years.
  • Depression (not including bipolar disorder) is the leading cause of disability among men and women of all ages in the U.S. and worldwide, according to the World Health Organization's World Health Report, 2001.


The majority of people with depressive disorders improve when they receive appropriate treatment. The first step to getting treatment is a physical examination by a physician to rule out other possible causes for the symptoms. Next, the physician should conduct a diagnostic evaluation for depression or refer the patient to a mental health professional for this evaluation.

Treatment choice will depend on the patient's diagnosis, severity of symptoms, and preference. A variety of treatments, including medications and short-term psychotherapies (i.e., "talking" therapies), have proven effective for depression. In general, severe depressive illnesses, particularly those that are recurrent, will require a combination of treatments for the best outcome. It usually takes a few weeks of treatment before the full therapeutic effect occurs. Once the person is feeling better, treatment may need to be continued for several months-and in some cases, indefinitely-to prevent a relapse.


Mental Disorders Account for Large Percentage of Adult Role Disability

An NIMH-funded study finds that more than half of U.S. adults have a mental or physical condition that prevents them from working or conducting their usual duties (e.g., role disability) for several days each year, and a large portion of those days can be attributed to mental disorders. The study, published in the October 2007 issue of the Archives of General Psychiatry, is based on data from the National Comorbidity Survey Replication (NCS-R), a nationwide survey among 9,282 Americans ages 18 and older.

Role disability is increasingly recognized as a major source of the societal costs of illness, but these indirect costs—the result of impaired functioning and lost productivity—are not easily measured, making it difficult to estimate the total costs of illness. To help quantify these costs, NIMH researcher Kathleen Merikangas, PhD., Ronald Kessler, PhD., of Harvard University, and colleagues analyzed data from 5,962 respondents of the NCS-R to determine the rate and frequency of role disability. They asked respondents how many days they were completely unable to work or carry out their usual activities as a result of a mental or chronic physical condition, such as an anxiety or mood disorder, substance or alcohol dependence, cancer, cardiovascular illness, musculoskeletal conditions, or others.

They found that over a one-year period, 53 percent of U.S. adults have one or more mental or physical conditions that result in role disability. Among those adults, each experienced an average of 32 days of disability per year. Nationwide, about 2.4 billion disability days resulted from physical conditions, and about 1.3 billion disability days resulted from mental conditions. “These figures suggest an enormous burden on the people who have one or more of these conditions, their families and their employers,” said Dr. Merikangas.

Estimating the impact of specific diseases on disability is difficult because people tend to have more than one illness or disorder at a time, such as depression and heart disease. By accounting for the likelihood of coexisting disorders, the authors found that musculoskeletal disorders, especially back and neck pain, resulted in the greatest number of disability days (1.2 billion) while major depression resulted in the second greatest number of disability days (387 million).

This research documents that the level of disability associated with chronic mental conditions is as large as that associated with many chronic physical conditions.  By documenting the impact and cost of chronic mental and physical disorders, this research may be useful to health care providers and policymakers.


Depression’s Flip Side Shares its Circuitry

Humans tend to be overly optimistic about the future, sometimes underestimating risks and making unrealistic plans, notes NIMH grantee Elizabeth Phelps, Ph.D., New York University. Yet "a moderate optimistic illusion" appears to be essential for maintaining motivation and good mental health.

Using functional magnetic resonance imaging (fMRI), Phelps and her colleagues have now shown that such "optimism bias" may be rooted in the same brain circuitry as depression, which is marked by a tendency to be overly pessimistic.

The same circuitry was also in play when this normal bias toward positive thinking was temporarily turned off by depriving the brain of the mood-regulating chemical messenger serotonin, in another recent fMRI study by NIMH intramural research psychiatrist Wayne Drevets, M.D., and colleagues.

Through this circuit, the anterior cingulate, just behind the front of the brain, regulates the amygdala, an emotion hub deep in the brain.Phelps and colleagues reported their findings in the October 24, 2007 issue of Nature.

They set out to discover why, for example, people tend to expect to live longer than average, underestimate their chances of getting a divorce and overestimate their likelihood of successful careers.

Fifteen healthy volunteers were scanned while they were remembering or imagining future events – like "winning an award" and "the end of a romantic relationship" – to see how their brain activity related to their ratings of these experiences and their scores on standard scales of optimism.

True to form, the participants rated future positive events as more vivid and expected them sooner than negative ones.

The cingulate/amygdala circuit showed more activity and connectivity with optimistic than with negative imaginings. The higher an individual scored on rating scales of optimism, the more an area at the front of the cingulate (see graphic below) activated. This rostral anterior cingulate appears to be the seat of these judgments, where emotional, motivational and autobiographical information is weighed – with an eye for the positive.

But the same circuit has a flip side. Citing an earlier study by Drevets and colleagues, Phelps's team pointed out that this cingulate/amygdala circuit may also underlie the pessimism and impaired imagining seen in depression.

In the recent study by Drs. Drevets, Jonathan Roiser, and colleagues, healthy volunteers who had never been depressed lost their optimism bias and showed brain activity changes in similar regions to Phelps and colleagues when they lacked tryptophan, the precursor chemical that the body uses to make the chemical messenger serotonin.

This first fMRI study to document neural and behavioral responses to emotionally-charged words when the healthy brain is starved of serotonin was published online September 19, 2007 in Neuropsychopharmacology.

Researchers had previously shown that people with a history of depression experience mood symptoms following such serotonin depletion, along with alterations in emotion-regulating brain circuits.

In the current study, 20 healthy participants initially made significantly more inappropriate responses to positive words while performing a task that required them to respond only to negative words, indicating that their attention was grabbed by the positive words – the optimism bias. However, after they took capsules containing essential amino acids, minus tryptophan, depriving their brains of serotonin, this normal bias toward positive words disappeared.

fMRI scans revealed that this loss of focus on the positive was accompanied by decreased cingulate activity in response to positive stimuli, particularly in a region toward the back of the cingulate cortex that was also implicated in the Phelps study. Drevets and colleagues have proposed that by taking the breaks off the amygdala, such decreased cingulate activity may play a role in depression.
By helping to accentuate the positive, serotonin, which is enhanced by antidepressants, may provide resilience in the face of life's hard knocks, suggest the researchers.

An area at the top front of the cingulate (yellow area in red circle) activated more when subjects imagined positive than negative future events. Activation was especially strong in subjects who scored high on scales of optimism. The researchers propose that this rostral anterior cingulate cortex weighs emotional, motivational and autobiographical information with an eye for the positive. Evidence suggests that decreased anterior cingulate regulation of the amygdala and other emotion hubs deep in the brain may be at the root of depression.
Source: Elizabeth Phelps, Ph.D., New York University

Much Touted “Depression Risk Gene” May Not Add to Risk After All

New Look at Data Confirms Strong Association between Depression and Stressful Life Events

Stressful life events are strongly associated with a person's risk for major depression, but a certain gene variation long thought to increase risk in conjunction with stressful life events actually may have no effect, according to researchers funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. The study, published in the June 17, 2009, issue of the Journal of the American Medical Association, challenges a widely accepted approach to studying risk factors for depression.

"Rigorous re-evaluations of published studies provide the checks and balances necessary for scientific progress," said Thomas R. Insel, M.D., director of NIMH. "We are still in the early days of understanding how genes and environment interact to increase the risk for depression."

Most mental disorders are thought to be caused by a combination of many genetic risk factors interacting with environmental triggers. However, finding the exact combinations continues to present significant challenges to research.

Advances in scientific understanding and technologies during the past decade have led to powerful tools for studying how genetic and environmental factors can affect a person's risk for disease. Such advances allowed mental health researchers in 2003 to show that a gene involved in serotonin activity increased the risk of major depression in people who had a number of stressful life events over a five-year period (see "More About the Science" below for more information about this gene and serotonin). Coming at a time of heightened research interest in these gene-environment interactions and the relative lack of progress in the field for mental disorders, this study received wide acclaim and had a far-reaching influence. Not only have considerable resources been invested in subsequent studies that built on this finding, but also some researchers have proposed marketing the gene test to the public, claiming to be able to predict a person's risk for depression.

However, efforts to replicate the 2003 study's findings—a key step in scientific progress that helps show whether a particular finding was a chance event—have had inconsistent results.

To examine whether the 2003 study's finding had been confirmed, a group of scientists from NIMH and six universities with expertise in epidemiology, biostatistics, genetics, and psychiatry reviewed the status of relevant replication studies. Led by Kathleen Merikangas, Ph.D., of the NIMH Intramural Research Program, the workgroup did a meta-analysis, re-analyzing data on 14,250 participants in 14 studies published from 2003 through March 2009. Of these, the researchers also re-analyzed original data, including unpublished information, on 10,943 participants from 10 studies published before 2008. The workgroup analyzed these original data to see whether there were gender differences in the associations between the serotonin genotype, stressful life events, and depression.

By applying the same definitions of study variables and data analysis methods used in the 2003 study, the workgroup found a strong association between the number of stressful life events and risk of depression across the studies. However, the presumed high-risk version of the serotonin transporter gene did not show a relationship to increased risk for major depression, alone or in interaction with stressful life events, in the analysis of the 14 studies. Their findings were the same in men and women alone in the analysis of original data from 10 studies.

The workgroup noted that their analysis had some limitations. Individual level data were available for only 10 of the 14 studies published before 2008. However, these limitations would have had little effect on the overall findings because the number of participants in the studies not included was only a small proportion of the total sample.

These findings may account for the difficulty many researchers have faced in attempting to replicate the 2003 study. This analysis confirms some earlier reviews that had also questioned the validity of the gene's effect on depression risk. However, the workgroup emphasized that the intent of its analysis was not to deter research on gene-environment interactions for mental disorders.

"Identifying gene-environment interactions is most successful when studies can focus on a single gene with a major effect, or when the environmental exposure has a strong effect," said lead author Neil Risch, Ph.D., University of California, San Francisco and Kaiser Permanente Northern California. "In the case of modest gene effects or environmental impacts, the statistical power to detect an interaction will be low, and thus weak positive results should be interpreted carefully."

The authors concluded that incorporating environmental exposures in candidate gene studies (those that study a particular gene) may be as likely to yield false positive findings as the candidate gene studies themselves. Therefore, the results of other studies using the same approach as the 2003 study also deserve thorough review and meta-analysis.

"Even though our re-analysis did not confirm an association between the serotonin gene and depression, the finding that the environmental factor was strongly associated with depression in several studies reminds us that environmental factors are also involved in the complex pathways leading to mental disorders," noted Merikangas. "Future progress will require thoughtful integration of the tools of genetics, epidemiology, and clinical and behavioral sciences."

More About the Science

Serotonin is one of several chemical messengers in the brain, or neurotransmitters, which help brain cells communicate with one another. Among many other functions, serotonin is involved in regulating mood. Problems with making or using the right amount of serotonin have been linked to many mental disorders, including depression, bipolar disorder, anxiety disorder, autism, and schizophrenia.

There are many genes that code for serotonin. Some of these genes guide serotonin production and other are involved in its activity. The serotonin transporter gene makes a protein that directs serotonin from the space between brain cells-where most neurotransmitters are relayed from one cell to another-back into cells, where it can be reused. Since the most widely prescribed class of medications for treating major depression acts by blocking this transporter protein, the gene has been a prime suspect in mood and anxiety disorders.

The serotonin transporter gene has many versions. Since everyone inherits a copy of this gene from each parent, a person may have two copies of the same version or one copy each of two different versions. One version of the serotonin transporter gene makes less protein, resulting in decreased transport of serotonin back into cells. This version has also long been the focus of depression research due to its suggested effect on risk.

Read more about NIMH research on depression and genetic risk factors


Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR. Interaction between the Serotonin Transporter Gene, Stressful Life Events and Risk of Depression: A Meta-Analysis. JAMA. 2009 Jun 17;301(23):2462-71.

Research Shows How Chronic Stress May be Linked to Physical and Mental Ailments

While scientists have long known that the levels of certain hormones rise in response to chronic stress, an NIMH study is the first to describe a potential fundamental mechanism for this process. Published in the February 2, 2009 issue of the Proceedings of the National Academy of Sciences, the findings reveal how individual cells adapt to cope with sudden or extreme stress, and how repeated exposure to stress may be related to many physical and mental illnesses.


Cortisol, a type of hormone called a glucocorticoid, plays a key role in the human brain's ability to adapt and recover from injury. It also plays a part in getting hormone receptors to the right places, where brain chemicals exert their effects.
In rats, corticosterone acts the same way as cortisol does in humans. Recent rat studies suggest that glucocorticoid receptors (GRs) move into mitochondria, energy-producing structures inside cells, in response to corticosterone. However, the research has not previously shown how this process occurred, or how it may affect mitochondrial or overall cell function.

Findings of This Study

Jing Du, M.D., Ph.D., of the NIMH Mood and Anxiety Disorders Program (MAP), along with Husseini Manji, M.D., former director of MAP, and colleagues found that in brain cells of rats treated with corticosterone, GR latched onto Bcl-2, a protein that affects how substances get in and out of mitochondria. The GR/Bcl-2 complex moves into the mitochondria and regulates mitochondrial functions.Brief increases of corticosterone enhance mitochondrial functions. However, the researchers found that high doses or long-term treatment with corticosterone led to decreased levels of GR and Bcl-2 in mitochondria. Similar results occur in rats exposed to chronic stress.


The study results show that, at first, glucocorticoids like cortisol or corticosterone boost mitochondrial functions to provide cells with more energy for coping with and adapting to acute challenges. This process appears to be critical in allowing a person to act quickly in an emergency.However, chronic stress may lead to chronically elevated levels of glucocorticoids, which in turn may reduce cell functioning, via the interaction between GR/Bcl-2 and mitochondria. The decrease in proper cell function may be at the root of certain physical and mental illnesses.

What's Next

This finding may be relevant to research on a number of stress-related illnesses, including anxiety disorders, depression, and  post-traumatic stress disorder (PTSD), and suggests new pathways for improving treatments.

One Gene Overrides Another to Prevent Brain Changes that Foster Depression

For what appears to be the first time in humans, scientists have detected an interaction between genes that may help prevent brain changes that increase vulnerability to depression.

A variation on one gene affects how much of the brain chemical serotonin is available to brain cells.  This variation is thought to raise the risk of depression in people who carry it. But NIMH scientists found that a variation in another gene, which produces brain-derived neurotrophic factor (BDNF) – a substance that enables growth and health of brain cells – appears to prevent or offset the changes generated by the depression-fostering variant.

For now, the finding can help scientists track the biological roots of depression in the brain as they search for better treatments.  In the future, it could help clinicians identify patients who are at risk and need monitoring or treatment.

Results of the study were published online on March 12, in Molecular Psychiatry, by Lukas Pezawas, Daniel R. Weinberger, and colleagues from the National Institute of Mental Health, the Universities of Pittsburgh and Vienna, and Germany’s Central Institute of Mental Health.

Using brain imaging in a study of 111 healthy people, the researchers found that those with the depression-promoting gene variation had alterations in brain-cell networks known to regulate mood.  But those who had both the depression-promoting variation and the apparently protective variation did not have these alterations in brain-cell networks.

Not everyone who has the serotonin-related variation develops depression, a disorder thought to be caused by interactions between variations in many genes and life experiences, such as stressful events.  One variation in a single gene does not appear to cause the disorder.

In this study, the scientists examined healthy people, rather than depressed people, because the illness might have introduced factors that would have confused the results. The study was not meant to show whether people became depressed, but rather to show whether the gene variations resulted in brain changes that set the stage for depression, or protection from it, in the mood-regulating brain-cell networks.  

Further research may tell if the different variations actually translate into differences in rates of depression among their carriers.

More About the Science

Both of the variations are in genes shown by earlier studies to regulate brain functions and structures in which alterations appear to contribute to depression. 

The depression-promoting variation is in the serotonin system, which helps brain cells communicate through chemical signals.  The gene is called SLC6A4 and makes a protein that transports serotonin among brain cells.  The variation that has been associated with increased risk of depression is called the 5-HTTLPR “S” version.

The gene containing the variation that apparently overrides the negative effects of the first gene variation is called BDNF.  It makes a protein that promotes growth and maintenance of brain cells. The variation in this gene, VAL66MET, has two versions.  The one that appeared to be protective in this study is called the MET version.

Animal studies suggest that changes in serotonin signaling during brain development can lead to lifelong changes in mood.  But serotonin doesn’t act alone in brain cells; a normal function of the BDNF protein is to act as an intermediary.  When serotonin signaling occurs, BDNF mediates changes in molecular machinery that enables brain cells to send and receive chemical messages.

One possibility is that abnormalities occur in this interplay of the chemical serotonin and the BDNF protein during brain development, potentially causing mood-regulating brain circuits to go awry.  With the new finding, researchers have evidence that two genes encoding components of these systems interact in ways that affect vulnerability to depression – potentially increasing or decreasing the risk, depending on which versions of the genes are present.

As scientists map the interactions between the many gene variants and life experiences that influence the risk of depression, they identify new opportunities for prevention and treatment.

Thinning Tissue in Right Half of Brain Signals Increased Risk of Inherited Depression

In cases of familial depression, changes in tissue thickness in key brain structures in the right half of the brain may increase a person's risk for developing depression, according to NIMH-funded researchers. Similar changes in the left half of the brain were linked to the severity of a person's existing depression or anxiety symptoms.

Based on their findings, the researchers proposed a possible mechanism for how these brain changes affect depression risk in the April 14, 2009, issue of the Proceedings of the National Academy of Sciences.


Some types of depression run in families, and certain changes in brain structure and function have been observed in people with the disorder. However, until recently, scientists have been unclear on the exact relationship between these brain changes and depression.

Building on previous research with a three-generation study population, Myrna Weissman, Ph.D., and Bradley Peterson, M.D., both of Columbia University College of Physicians & Surgeons and New York State Psychiatric Institute, and colleagues used magnetic resonance imaging (MRI) to assess brain changes in 131 people, ages 6-54. Roughly half of these participants were considered at high risk for major depressive  disorder (MDD) due to having at least one parent or grandparent in the study diagnosed with the illness. The other half, considered at low risk, had no family history of the illness.

Results of the Study

From pre-scanning interviews, the researchers found that people in the high-risk group were more likely than those in the low-risk group to report having MDD or an anxiety disorder at some point in their lives. MRI scans showed that, on average, those in the high-risk group had 28 percent thinner brain tissue across a broad range of brain structures in the right half of the brain. These changes were observed in young children in the high-risk group and in older high-risk individuals who had never suffered from MDD or an anxiety disorder themselves.

The brain areas most affected by this thinning govern attention and the ability to process emotional or social cues (such as faces or family pictures). In tests involving these right-brain tasks, the researchers found that thinner tissue in these areas was linked to greater inattention and poorer performance in immediate and delayed visual memory.

Similar patterns of tissue thinning in the left half of the brain appeared to be related to the severity of a person's existing MDD or anxiety disorder symptoms in both the high- and low-risk groups. This thinning was not as pronounced as the thinning in the right half of the brain, and the difference in tissue thickness between the high- and low-risk groups was not statistically significant.


The findings strongly suggest that changes in tissue thickness in the right half of the brain directly affect a person's inherited risk for developing MDD. The pattern of tissue thinning appears to be related to problems with attention and processing of emotional or social signals. Such problems may increase a person's vulnerability to developing mood or anxiety disorders, according to the researchers.

That the thinning was present in people at high risk, but who had never had MDD or an anxiety disorder, as well as in high-risk children who had not been diagnosed with depression, shows that these brain changes likely come before illness onset and that they occur very early in life, possibly before birth, say the researchers. Furthermore, while thinning in the right half of the brain contributes to risk, thinning in the left half of the brain appears to be required in order for a person to show symptoms of these illnesses.

What's Next

More research is needed to determine if the inherited risk for MDD is purely genetic, if there are specific environmental factors necessary for triggering genetic risk, or whether there is a combination of factors involved. Increased understanding of how risk translates into developing MDD or other mental disorders may lead to new methods of diagnosing, treating, or preventing these illnesses.

Top: Color coded MRI brain maps of differences in tissue thickness between study participants at high- vs. low-risk for familial depression. Left half of brain is shown on the left and right half on the right. Cool colors (blue and purple) denote thinner areas in the high-risk group; warm colors (yellow, orange, and red) are significantly thicker areas; green areas show little to no difference in tissue thickness.

Bottom: Flowchart represents a proposed model for how some MDD or anxiety disorders develop. Double-headed arrows indicate factors that may influence each other and jointly contribute to disease risk. Block arrows show the hypothetical progression from inherited risk to development of symptoms.
Source: Bradley Peterson, M.D., Columbia University College of Physicians & Surgeons and New York State Psychiatric Institute

Depression Patients’ Brain Circuitry Makes Them Vulnerable to Relapse

Using brain imaging, NIMH researchers have produced direct evidence that people prone to depression -- even when they're feeling well -- have abnormal mood-regulating brain circuitry. This makes them vulnerable to relapse when levels of certain key brain chemical messengers plummet.

Wayne Drevets, M.D., of the NIMH Mood and Anxiety Disorders Program, Gregor Hasler, M.D., now at University Hospital, Zurich, Switzerland, and colleagues reported on their positron emission tomography (PET) scan study in the May 2008 Archives of General Psychiatry.

Indirect evidence had suggested that people with histories of depression have such a "trait abnormality" in brain systems that communicate using the brain chemicals dopamine and norepinephrine. Decreased dopamine activity, in particular, is thought to be associated with depression.

To test this directly and identify any brain circuit abnormalities, the researchers studied 15 un-medicated subjects in remission who had a history of depression by giving them a drug that temporarily depleted their brains of dopamine and norepinephrine.

These subjects experienced an increase in depression symptoms and a decrease in the ability to feel pleasure. PET scans showed that this was accompanied by an increase in activity in a depression-implicated brain circuit. By contrast, activity decreased or remained unchanged in the same brain circuit with depletion in 13 healthy participants who experienced only minor mood effects. Activity in specific brain structures in the circuit corresponded with a set of mood effects.

Dopamine normally functions in the circuit to inhibit runaway activity of emotion hubs deep in the brain by higher brain centers. Depleting dopamine effectively takes the brakes off the emotional hubs in depression-prone individuals - hence the increased circuit activity, the researchers suggest.

"The subjects in remission from depression experienced symptoms qualitatively similar to those they had during major depressive episodes," said Drevets. "Our findings suggest that depression is associated with persistent vulnerability for developing such responses to reduced dopamine and norepinephrine neurotransmission."

Depressive Symptoms

Increased activity in an area in the lower middle of the front of the brain correlated with depression symptoms experimentally induced by a drug that depleted dopamine and norepinephrine.
Source: Wayne Drevets, M.D., NIMH Mood and Anxiety Disorders Program

Loss of Ability to Experience Pleasure

Studies Identify Subtle Genetic Changes’ Risk for Mental Disorders; May Lead to Targets for New, Better, Therapies

Epigenetics — the examination of how environmental factors like diet, stress, and post-natal maternal behavior can change gene function without altering DNA sequence — plays a major role in depression and in the actions of antidepressant medications. New studies in the field are revealing new molecular targets for better therapies for depression, scientists say.

They spoke at a press conference today following a National Institute of Mental Health (NIMH)-sponsored symposium on epigenetics during the American Psychiatric Association Annual Meeting here. NIMH is a part of the National Institutes of Health.

"The mechanisms that precipitate depression, such as stress, are incompletely understood," says Eric Nestler, MD, PhD, of The University of Texas Southwestern Medical School in Dallas, and organizer of the symposium. "One mystery of the disease is its long-lasting nature and delayed response to antidepressant treatment. This persistence is thought to be influenced by slowly developing but stable adaptations, which might include epigenetic regulation."

Unlike mutations, epigenetic changes aren't variations in the sequences of building blocks that make up the DNA in a gene. The genes remain stable, but environmental factors — such as stress, diet and maternal care received early in life — act on the supporting structures of DNA, such as chromatin, molecules that package genes into chromosomes. Certain chemical reactions can unravel the chromatin, causing the DNA code that comprises a gene to be exposed for longer or shorter periods of time, essentially turning the gene on or off, and allowing it to produce more or less protein. This change in protein production, in turn, can affect physical and behavioral traits, and can be passed on from one cell to the next as they multiply within an organism, and even from parents to children.

Depression is a common, chronic and debilitating disease that affects more than 15 million Americans. Although many patients benefit from antidepressant medications, psychotherapy and other treatments, not all patients respond to treatment. This underscores the need for more effective agents.

The recent epigenetic studies in depression are a high priority for the field because they allow characterization of important changes in chromatin mechanisms that occur in the brain of animal models of depression during antidepressant treatment, and in studies of human postmortem brain tissue.

Subtle Changes Traced to Depression-Like Symptoms

At a molecular level, Nestler* and his colleagues have found changes in chromatin remodeling in particular genes in brain areas known as the nucleus accumbens and hippocampus in response to chronic social stress.

"In both brain regions, we have been able to directly relate these chromatin changes to some of the behavioral abnormalities observed," says Nestler. In animal models of chronic stress, Nestler and his colleagues manipulated chromatin in these brain areas in ways that produced antidepressant-like effects.

This work provides new insight into the molecular mechanisms by which chronic stress produces lasting changes in specific brain areas to cause depression-like symptoms, says Nestler. The findings also suggest new leads for the development of new antidepressant treatments.

Modifications Enhance Therapeutic Response

In other studies, Schahram Akbarian, MD, PhD, and his colleagues at the University of Massachusetts Medical School in Worcester, MA, are studying changes in methylation, a type of chemical modification of the DNA and of histones, the protein "backbone" of chromatin.

"We found that these chemical modifications in brain chromatin are dynamically regulated from the perinatal period to old age, and could be involved in epigenetic control of gene expression, including genes for brain-derived neurotrophic factor and others implicated in mood and anxiety spectrum disorders," says Akbarian.

His epigenetic findings may have direct implications for the design of novel antidepressant treatment strategies. Preliminary findings from studies in mice in Akbarian's laboratory indicate that chemical modification of epigenetic-related factors could enhance the therapeutic response to frequently prescribed antidepressant drugs such as fluoxetine (Prozac) or monoamine oxidase inhibitors.

These findings also suggest that a better understanding of epigenetic and other "non-genetic" mechanisms operating in the human and animal brain may, in the future, lead to better treatment options for patients diagnosed with a major mood disorder.

Maternal Care Affects Behavior

Michael Meaney, PhD, of McGill University in Montreal, reports how early maternal separation alters the methylation state of specific genes in the rodent hippocampus, and triggers long-lasting behavioral effects.

Meaney and his colleagues have found that differences in maternal care, such as grooming and licking, can change how rat pups' behavioral and hormonal response to stress develops. This leads to persistent lifelong changes in the pups' response to stress and how they process information about stressors.

"This may reveal experience-dependent adaptability in the chemistry of the DNA and chromatin structure," Meaney says


Suicidal Thinking May Be Predicted Among Certain Teens with Depression

Certain circumstances may predict suicidal thinking or behavior among teens with treatment-resistant major depression who are undergoing second-step treatment, according to an analysis of data from an NIMH-funded study. The study was published online ahead of print February 17, 2009, in the American Journal of Psychiatry.

In the Treatment of SSRI-resistant Depression in Adolescents (TORDIA) study, 334 teens who did not get well after taking a type of antidepressant called a selective serotonin reuptake inhibitor (SSRI) before the trial were randomly assigned to one of four treatments for 12 weeks:

  • Switch to another SSRI
  • Switch to venlafaxine (Effexor), a different type of antidepressant
  • Switch to another SSRI and add cognitive behavioral therapy (CBT), a type of psychotherapy
  • Switch to venlafaxine and add CBT

Results of the trial were previously reported in February 2008. They showed that teens who received combination therapy, with either type of antidepressant, were more likely to get well than those on medication alone.

Using data from spontaneous reports by the participants and from systematic assessment by clinicians, David Brent, M.D., of the Western Psychiatric Institute and Clinic, and colleagues aimed to identify characteristics or circumstances that may predict whether a teen is likely to have suicidal thoughts or behavior during treatment. Nearly 60 percent of TORDIA participants had suicidal thinking or behavior at the beginning of the trial.

Fifty-eight suicidal events—which include serious suicidal thinking or a recent suicide attempt—occurred in 48 participants during the trial, most of which happened early in the trial. The researchers found that teens who had higher levels of suicidal thinking, higher levels of parent-child conflict, and who used drugs or alcohol at the trial's beginning were more likely to experience a suicidal event during treatment and less likely to respond to treatment. They were also less likely to have completed treatment.

"These new data may contribute to developing more targeted and individualized interventions." said NIMH co-author Benedetto Vitiello, M.D. "If we can know which teens may be more susceptible to suicidal thinking and behavior, we are better able to tailor safer treatments for them."

No statistically significant differences in suicidal events or non-suicidal self-injury were found among the treatment options. However, the use of venlafaxine was associated with a higher rate of self-injury in participants who had more severe suicidal thinking at the trial's beginning. These results suggest that SSRIs are preferred over venlafaxine in the treatment of depressed teens who are at risk for suicidal thinking or behavior, according to the researchers.

Although CBT was found to have a protective effect over the long-term among teens with depression in the NIMH-funded Treatment for  Adolescents with Depression Study (TADS), it did not appear to reduce the rate of suicidal events in TORDIA. The researchers theorize that because the suicidal events tended to occur soon after treatment began, the CBT did not have enough time to deliver a protective dose.

Finally, Brent and colleagues found that the use of anti-anxiety medications called benzodiazepines was associated with a higher likelihood of, and faster time to, a suicidal event—an unexpected result not found in other similar studies. The researchers theorize that participants who were taking a benzodiazepine in addition to an antidepressant may have been much more severely ill and therefore may have been more prone to suicidal thoughts or behavior. But more study is warranted on the potential role of anti-anxiety medications in suicidal thinking and actions among patients also taking an antidepressant.

"Because the suicidal events tended to happen early in the treatment process, interventions that address safety, emotion regulation and family conflict should be some of the first to be implemented," concluded Dr. Brent. "With this data, we are in a better position to design future interventions that could lessen the risks of suicide even further among this vulnerable population."


Odds of Beating Depression Diminish as Additional Treatment Strategies are Needed

An overall assessment of the nation's largest real-world study of treatment-resistant depression suggests that a patient with persistent depression can get well after trying several treatment strategies, but his or her odds of beating the depression diminish as additional treatment strategies are needed. The conclusions from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, funded by NIMH, were published in the American Journal of Psychiatry on November 1, 2006.

The analysis also found two important indicators of treatment success. Those who become symptom-free have a better chance of remaining well, as measured in the follow-up period, than those who experience only symptom improvement. Those who need to undergo several treatment steps before they become symptom-free are more likely to experience a relapse during the one-year follow-up phase, reminding clinicians that even if a patient overcomes the depression, he or she still needs attention. These results underscore both the need for a better understanding of how different people respond to different depression treatments, and the challenges in finding broadly effective, short- and long-term depression treatments.

"This new STAR*D report reminds us that treating depression remains a formidable challenge," said NIMH Director Thomas Insel M.D. "While roughly two-thirds of patients report remission, many subsequently relapse. We need new treatments that are rapid, enduring, and individualized to facilitate recovery."

The paper examined all four medication levels of the STAR*D trial. About half of the participants became symptom-free after the first two treatment levels. After that, rates at which participants beat their depression  slowed. Over the course of all four levels, about 70 percent of those who did not withdraw from the study became symptom-free.

Those who required more treatment levels tended to have more severe depressive symptoms, and more co-existing psychiatric and general medical problems at the beginning of the study than those who became well after just one treatment level. In addition, the rate at which participants withdrew from the study rose with each level—21 percent withdrew after level 1, 30 percent withdrew after level 2 and 42 percent withdrew after level 3.

"Clinicians need to pay particular attention to those patients with chronic depression and identify any co-existing conditions that may be exacerbating the depression or interfering with treatment," said lead author A. John Rush, M.D. of the University of Texas Southwestern Medical Center. "They need to closely monitor both the symptoms and side effects of these most vulnerable patients throughout treatment and suggest different treatment strategies when needed. Diligent follow-up, even after a patient becomes symptom-free, is essential to avoid relapse."

The STAR*D trial provides robust, real-world data that can be applied broadly to both primary and specialty care settings. The study confirms that different people respond to different treatment strategies, but it does not pinpoint what treatments work best for whom. The STAR*D team concluded that future research should be targeted to identify the best multi-step treatment options for individuals, especially those with treatment-resistant depression.

Premature Birth Risk Higher for Pregnant Women Taking SSRIs or Suffering from Untreated Depression

Untreated major depression, as well as the use of antidepressant medications, may increase the risk for premature (preterm) birth, but the risk of other problems in fetuses such as breathing, gastrointestinal, or motor problems, may not be increased, according to a study of pregnant women published online ahead of print March 15, 2009, in the American Journal of Psychiatry.


Use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), is common among women of childbearing age. Although there is some concern regarding the use of SSRIs during pregnancy and their effects on the growing fetus, research results have been mixed. Overall, it appears the risk for major birth defects is very low, but the risk for other complications, such as minor physical anomalies—a specific type of birth defect—or preterm birth (before 37 jeannaweeks gestation), has not been consistently established.

Katherine L. Wisner, M.D., of the University of Pittsburgh, and colleagues aimed to determine whether the use of SSRIs or the existence of major depression during pregnancy was associated with minor physical anomalies in the baby, low infant birth weight, preterm birth or other issues. In this observational study, the researchers categorized 238 pregnant women in Cleveland, Ohio, and Pittsburgh, Pa., into one of three groups:

  • no use of SSRIs and no major depression during pregnancy (131 women);
  • use of SSRIs either at some point (23 women) or throughout the pregnancy (48 women);
  • those who had major depression—either at some point (22 women) or throughout the pregnancy (14 women)—but who remained unmedicated.
The researchers gave general advice to the women about managing major depression and use of SSRIs, but they did not interfere in treatment decisions made by the women and their doctors. Wisner and colleagues examined various outcomes, such as maternal weight gain, pregnancy duration, minor physical anomalies in the infant, infant birth weight, and other infant characteristics.

Results of the Study

Wisner and colleagues found that for both pregnant women with untreated major depression and for those who were taking SSRIs throughout their pregnancy, more than 20 percent of infants were delivered preterm. In comparison, only 4 percent of infants partially exposed to SSRIs during gestation and 6 percent not exposed at all to SSRIs or depression during gestation were delivered pre-term.
Neither the use of SSRIs nor major depression was associated with an increase in minor physical anomalies; short-term medication-associated issues like breathing, gastrointestinal or motor problems; or reduced weight gain among the women during pregnancy. Birth weight of infants also did not differ across groups.


The results support other studies that have found a link between continuous SSRI treatment and an increase in risk of preterm birth, but they are not consistent with studies that have found an increased risk of drug-associated issues in infants exposed to SSRIs while in the womb. However, the researchers note that untreated depression among pregnant women may present the same risk to infants as SSRI use, reiterating the need for doctors to work with individual patients to balance the risks and benefits of SSRI use and the treatment of major depression during pregnancy.

What's Next

More research is needed to better determine whether women with major depression who are treated with SSRIs and experience remission during pregnancy have more favorable outcomes compared to unmedicated depressed women. In addition, larger studies may be able to determine differences in outcomes among SSRIs. Finally, more research into non-medication interventions for treating depression during pregnancy, including psychotherapy and other approaches, is also needed.

Co-occurring Anxiety Complicates Treatment Response for Those with Major Depression

People with major depression accompanied by high levels of anxiety are significantly less likely to benefit from antidepressant medication than those without anxiety, according to a study based on data from the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The study was published online ahead of print in January 2008, in the American Journal of Psychiatry.

The STAR*D trial examined four levels of treatment for difficult-to-treat depression, all of which tested different medications and medication combinations. Results from the four levels of treatment are available.

This new study is the largest to date to determine if people with major depression and co-occurring high levels of anxiety respond differently to treatment than those without co-occurring anxiety. Maurizio Fava, M.D., of Massachusetts General Hospital, and colleagues examined response and remission rates among the 53 percent of STAR*D participants (1530 of the 2876 participants treated in the first two treatment steps) who were identified as having “anxious depression”—major depression coupled with significant symptoms of anxiety.

During Level 1 treatment, 42 percent of those with anxious depression responded to treatment and got somewhat better, compared to 53 percent of those without anxiety. Among those who remitted, or became symptom-free, rates were much lower—only 22 percent of those with anxious depression became symptom-free, compared to 33.4 percent of those without anxiety.

In Level 2 treatment, when participants who did not respond in Level 1 could either switch to another antidepressant or add another to the existing one, participants with anxious depression fared significantly worse than those without anxiety, regardless of whether they switched or added medication. They also experienced more frequent and more severe side effects from the medications.

The researchers also found that those with anxious depression were more likely to be unemployed, have less education, have more severe depression, have suicidal thoughts, and have more coexisting illnesses, both medical and psychiatric. They were more likely to be hospitalized during the trial, as well.

The results are consistent with previous research showing that people with depression and high levels of anxiety are less likely to respond to antidepressant medication, regardless of what medication is used. They also may lead to more recognition and possible diagnosis of anxious depression. “Clinicians should be aware of a patient’s sociodemographic situation and take note if he or she shows significant anxiety along with depression," said Dr. Fava. "The combination likely warrants a more personalized treatment approach.”

In addition to antidepressants, high levels of anxiety may be treated with anti-anxiety medications such as benzodiazepines or beta-blockers, and with psychotherapy. More information about treatment options for anxiety is available here.


Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels

1. What were the goals of the STAR*D trial?

A. The overall goal of the STAR*D trial was to assess the effectiveness of depression treatments in patients diagnosed with major depressive disorder, in both primary and specialty care settings. It is the largest and longest study ever conducted to evaluate depression treatment.

Each of the four levels of the study tested a different medication or medication combination. The primary goal of each level was to determine if the treatment used during that level could adequately treat participants’ major depressive disorder (MDD). Those who did not become symptom-free could proceed to the next level of treatment.

The design of the STAR*D study reflects what is done in clinical practice because it allowed study participants to choose certain treatment strategies most acceptable to them and limited the randomization of each participant only to his/her range of acceptable treatment strategies. No prior studies have evaluated the different treatment strategies in broadly defined participant groups treated in diverse care settings.

2. Who participated in the study?

A. Over a seven-year period, the study enrolled 4,041 outpatients, ages 18-75 years, from 41 clinical sites around the country, which included both specialty care settings and primary medical care settings. Participants represented a broad range of ethnic and socioeconomic groups. All participants were diagnosed with MDD and were already seeking care at one of these sites. No media advertisements were used to recruit participants. Instead, they were referred to the trial by their doctors.

So that results could be generalized to a broad group of real-world patients, most adults with MDD were eligible. People were not eligible for the study if they had not tolerated or did not get well with one or more of the treatments that were part of the first two STAR*D treatment steps, or if a STAR*D treatment could not be safely used because of another medical condition or because they were taking certain other medications. In addition, people with substance abuse disorders that required detoxification, anorexia or bulimia, or obsessive compulsive disorder were not eligible for the study because they required treatments that were not part of STAR*D.

Of the initial 4,041 participants, 1,165 were excluded because they either did not meet the study requirements of having “at least moderate” depression (based on a rating scale used in the study) or they chose not to participate. Thus, 2,876 “evaluable” people were included in level 1 results. Level 2 results include 1,439 people who did not become symptom-free in level 1 and chose to continue. Level 3 results include 377 people, and Level 4 results include 142 people.

3. What were the treatments used in the study?

A. In level 1, participants were given the antidepressant citalopram (Celexa) for 12 to 14 weeks. Those who became symptom-free during this time could move on to a 12-month follow-up period during which the citalopram was continued, and patients were monitored. Those who experienced intolerable side effects or did not become symptom-free during this level could go on to level 2.

Citalopram is representative of the class of antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs). It was chosen as the first treatment because it generally is not associated with troublesome withdrawal symptoms when it is stopped, is easy to administer (once a day), and has been shown to be safe for older adults and medically fragile patients. It does not appear to interact unfavorably with other medications that some participants may have been taking for other medical problems.

Level 2 was designed to help determine an appropriate next treatment step if the first step did not work. Thus, in level 2, participants had the option of switching to a different medication or adding on to their existing citalopram.

Those who joined the “switch” group were randomly assigned to either sertraline (Zoloft), bupropion-SR (Wellbutrin), or venlafaxine-XR (Effexor). These medications were chosen for comparison because they represent three different types of medications. Sertraline is an SSRI, the same class as the citalopram used in level 1. Bupropion belongs to another class of antidepressant medications that work on different neurotransmitters than SSRIs. Venlafaxine is a “dual-action” medication that works on two neurotransmitters at the same time.

Those who joined the “add-on” group were prescribed either the non-SSRI antidepressant bupropion-SR (Wellbutrin), or buspirone (BuSpar), which is not an antidepressant but enhances the action of an antidepressant medication. Participants could also switch to, or add on, cognitive psychotherapy.

As in level 1, those who became symptom-free with their level 2 treatment could continue with that treatment and entered the follow-up period. Those who did not become symptom-free, or who experienced intolerable side effects, could continue on to level 3.

In level 3, which like level 2 was designed to compare medications that are thought to work differently in the brain and produce different results, participants again had the option of either switching to a different medication or adding on to their existing medication. Those who chose to switch their medication were randomly assigned to either mirtazapine (Remeron) — a different type of antidepressant — or to nortriptyline (Aventyl or Pamelor) — a tricyclic antidepressant — for up to 14 weeks. Both work differently in the brain than the SSRIs and other medications used in levels 1 and 2.

In the level 3 add-on group, participants were randomly prescribed either lithium — a mood stabilizer commonly used to treat bipolar disorder — or triiodothyronine (T3) — a medication commonly used to treat thyroid conditions — to add to the medication they were already taking. These medications were chosen because they have been shown to boost the effectiveness of antidepressant medications.

In level 4, participants who had not become symptom-free in any of the previous levels (and therefore considered to have highly treatment-resistant depression) were taken off all other medications and randomly switched to one of two treatments — the monoamine oxidase inhibitor (MAOI) tranylcypromine (Parnate) or the combination of venlafaxine extended release (Effexor XR) with mirtazapine (Remeron). These treatments were chosen for comparison because previous research had suggested that they may be particularly effective in people who had not received sufficient benefit from other medications.

4. How were participant’s doses decided and how was their progress measured?

A. To ensure that every participant had the best chance of recovery with each treatment strategy, a systematic approach called measurement-based care was used. This method requires routine, consistent measurement of symptoms and side effects at each treatment visit with easy-to-use measurement tools. It also involves the use of a treatment manual that describes when and how to modify medication doses and dose adjustments to best tailor them for individual participants so as to minimize side effects, maximize safety, and provide the best chance of therapeutic benefit. This enabled STAR*D practitioners to provide consistent, high-quality care.

STAR*D employed easy-to-use rating tools of symptoms and side effects in a systematic and consistent way. These tools can readily be incorporated into real-world medical and psychiatric settings. Use of this measurement-based care may have caused greater than expected remission rates.

Patients were asked to self-rate their symptoms. The study demonstrated that most depressed patients can quickly and easily self-rate their symptoms and estimate their side effect burden in a very short time. Their doctors can rely on these self-rated tools for accurate and useful information to make informed judgments about treatment. The patients can also use these tools to help manage their illness at home in much the same way that hypertensive patients can measure their own blood pressure.

5. What were the results?

A. In most clinical trials of treatment for depression, the measure of success (outcome) is called “response” to treatment, which means that the person’s symptoms have decreased to at least half of what they were at the start of the trial. In STAR*D, the outcome measure was a “remission” of depressive symptoms—becoming symptom-free. This outcome was selected because people who reach this goal generally function better socially and at work, and have a better chance of staying well than do people who only achieve a response but not a remission.

In level 1, about one-third of the participants reached remission and about 10-15 percent more responded, but did not reach remission. Still, these are considered good results because study participants had high rates of chronic or recurrent depression and other psychiatric medical problems.

It took an average of six weeks of treatment for participants to improve enough to reach a response and nearly seven weeks of treatment for them to achieve a remission of depressive symptoms. In addition, participants visited their care providers an average of five to six times. Participants who achieved remission stayed on the treatment for an average of 12 weeks before going on to a 12-month follow-up period.

In the level 2 switch group, about 25 percent of participants became symptom-free. All three of the switch medications performed about the same and were equally safe and well-tolerated. In the add-on group, about one-third of participants became symptom-free. Those who added bupropion experienced less troublesome side effects and slightly more reduction of symptoms than those who added buspirone.

In levels 2 and 3 where participants were allowed to either add-on or switch medications, most participants found only one or the other treatment strategies acceptable. Because most participants did not agree to be randomly assigned to one or the other treatment strategy, the findings of the add-on and switch approaches cannot be compared. It is likely, however, that people being treated in the real world also tend to limit their treatment preferences to switching or adding on medications. In addition, the people in the switch and add-on groups were a little different. The group who chose and were assigned to a switch medication had more problematic side effects while taking the preceding medication (citalopram) than the group who chose and were assigned to an add-on medication.

Level 2 also included cognitive psychotherapy as a switch or add-on treatment. Results for the psychotherapy treatment are not yet available.

In the level 3 switch group, 12 to 20 percent of participants became symptom-free, and the two medications used fared about equally well, suggesting no clear advantage for either medication in terms of remission rates or side effects. In the add-on group, about 20 percent of participants became symptom-free, with little difference between the two treatments. However, the T3 treatment was associated with fewer troublesome side effects than lithium.

In level 4, seven to 10 percent of participants became symptom-free, with no statistically significant differences between the medications in terms of remission, response rates or side effect burden. However, those taking the venlafaxine-XR/mirtazapine combination experienced more of a reduction in depressive symptoms than those taking the tranylcypromine. Also, those who were treated with tranylcypromine were more likely to discontinue the treatment citing side effects as the reason. It is also possible that the dietary restrictions associated with taking an MAOI could have limited its acceptability as a treatment.

In conclusion, about half of participants in the STAR*D study became symptom-free after two treatment levels. Over the course of all four treatment levels, almost 70 percent of those who did not withdraw from the study became symptom-free. However, the rate at which participants withdrew from the trial was meaningful and rose with each level—21 percent withdrew after level 1, 30 percent withdrew after level 2 and 42 percent withdrew after level 3.

6. What lessons are learned from the results?

A. For the first time, doctors and people with depression now have extensive data on antidepressant treatments from a federally funded, large-scale, long-term study directly comparing treatment strategies.

Results from level 2 indicate that if a first treatment with one SSRI fails, about one in four people who choose to switch to another medication will get better, regardless of whether the second medication is another SSRI or a medication of a different class. And if patients choose to add a new medication to the existing SSRI, about one in three people will get better. It appears to make some—but not much—difference if the second medication is an antidepressant from a different class(e.g. bupropion) or if it is a medication that is meant to enhance the SSRI (e.g. buspirone). Because the switch group and the add-on group cannot be directly compared to each other, it is not known whether patients are more likely to get better by switching medications or by adding another medication.

Results from level 3 apply to those who do not get better after two medication treatment steps. By switching to a different antidepressant medication, about one in seven people will get better. By adding a new medication to the existing one, about one in five people will get better. Level 3 results also tell us that adding T3 may have some advantages over adding lithium for patients who have tried two other treatments without success.

Finally, for patients with the most treatment-resistant depression, level 4 results suggest that tranylcypromine is limited in its tolerability and that up to 10 percent may benefit from the combination of venlafaxine-XR/mirtazapine.

An overall analysis of the STAR*D results indicates that patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish with every additional treatment strategy needed. In addition, those who become symptom-free have a better chance of remaining well than those who experience only symptom improvement. And those who need to undergo several treatment steps before they become symptom-free are more likely to relapse during the follow-up period. Those who required more treatment levels tended to have more severe depressive symptoms and more co-existing psychiatric and general medical problems at the beginning of the study than those who became well after just one treatment level.

These results underscore both the need for a better understanding of how different people respond to different depression treatments, and the challenges in finding broadly effective, short- and long-term depression treatments. Future research may help identify which treatments work for which patients.

7. What do the STAR*D results mean to people with MDD and their doctors?

A. The results reiterate the need for high-quality care and attention to the individual needs of patients. Doctors should provide medication at optimal doses, be aware of and offer treatment choices, and maintain diligent monitoring of patients both during treatment and after they become symptom-free so as to avoid relapse.

Like other medical illnesses, depression affects different people in different ways, but a wide range of effective treatments exist. People with depression should not give up if their initial treatment attempts do not result in full benefits. They should continue to work with their doctors to find the best treatment strategy.

In addition, patience is required. While some people may experience benefits in the first six weeks of a treatment strategy, full benefits may not be realized until 10 or 12 weeks have passed. During this time, doctors should work with their patients to adjust dosages so as to find an optimal level, and avoid stopping a treatment prematurely.

8. What more will be learned from the STAR*D study and what areas of future research will be influenced by STAR*D?

A. The STAR*D study results published to date provide important information about the effectiveness of current treatments in primary care and specialty settings in real world patients. Subsequent analyses of the STAR*D data include:

  • results of cognitive therapy as a switch and add-on treatment;
  • factors affecting patient preferences in choosing next-step treatments when a first treatment is not successful;
  • comparison of the effectiveness of different treatments in preventing relapse; and
  • factors associated with relapse.
Also, blood samples that were voluntarily collected from more than 1,900 of the STAR*D participants will allow researchers to identify potential biological markers of disease course and treatment response.

The results of STAR*D also underscore the need for more effective treatment strategies and more patient-tailored interventions for the treatment of major depression. Future research topics beyond STAR*D include:

  • developing methods to predict who will respond to which treatment and in what treatment sequence; and
  • evaluating combination medication strategies earlier in the course of treatment compared to single therapy strategies.

Getting Closer to Personalized Treatment for Teens with Treatment-resistant Depression

Some teens with treatment-resistant depression are more likely than others to get well during a second treatment attempt of combination therapy, but various factors can hamper their recovery, according to an NIMH-funded study published online ahead of print February 4, 2009, in the Journal of the American Academy of Child and Adolescent Psychiatry.


About 40 percent of teens with major depression do not get well after a first treatment attempt with an antidepressant medication. The NIMH-funded Treatment of Resistant Depression in Adolescents (TORDIA) study was designed to test second-step treatment strategies for these teens.

In TORDIA, 334 teens who did not get well after taking a type of antidepressant called a selective serotonin reuptake inhibitor (SSRI) before the trial were randomly assigned to one of four treatments for 12 weeks:

  • Switch to another SSRI
  • Switch to venlafaxine, a different type of antidepressant
  • Switch to another SSRI and add cognitive behavioral therapy (CBT), a type of psychotherapy
  • Switch to venlafaxine and add C

Results of the trial, which were reported in February 2008, showed that the teens who received medication plus CBT were more likely to get well than those who switched medications only. In this most recent data analysis, Joan Rosenbaum Asarnow, Ph.D., of the University of California Los Angeles, and colleagues aimed to identify how to better predict a teen's response to treatment, and any factors that might affect response.

Results of the Study                         

Many predictors were similar to those found in studies of first-step treatments, such as the NIMH-funded Treatment for  Adolescents with Depression Study (TADS), underscoring the importance of early treatment before the depression becomes chronic. For instance, like in TADS, teens in the TORDIA study were less likely to respond to treatment if they had very severe depression or higher levels of suicidal thinking. In addition, teens prone to self-harming behavior and family conflict were less likely to respond to treatment.

In contrast to TADS, however, the TORDIA teens with coexisting disorders, such as an anxiety disorder, attention deficit hyperactivity disorder (ADHD), or others, did respond to TORDIA's combination therapy. The researchers theorize that in this SSRI-resistant group, adding a CBT framework may have helped the teens deal with difficulties associated with coexisting disorders. In addition, the type of CBT used in the trial included general strategies for coping with a wide range of disorders, such as ways of solving problems and improving social functioning. Because community settings often must treat patients with coexisting disorders, this finding supports the use of CBT with patients who have complex diagnoses, according to the researchers.

Combination treatment, however, was not as beneficial for teens with a history of abuse, and those reporting high levels of hopelessness. This suggests a need to strengthen treatment strategies for teens suffering from these problems, said the researchers.


Knowing predictors and moderators of treatment response may help identify the most appropriate treatment for each individual.

"Selecting the optimal treatment for teens with depression is particularly crucial for those who do not respond to an initial treatment, because when depression is unremitting, teens and their parents often give up, which makes them less likely to stick to treatment," concluded Dr. Asarnow. "With this new data, personalizing depression treatment based on a teen's individual circumstances becomes a real possibility."

What's Next

Future studies can help confirm these findings and therefore contribute to a more personalized approach to the treatment of depression in adolescence. In addition, the researchers conclude that findings from this study can inform efforts to build better treatment strategies.

Depression Relapse Less Likely Among Teens Who Receive CBT After Medication Therapy

Adolescents with major depression who received cognitive behavioral therapy (CBT) after responding to an antidepressant were less likely to experience a relapse or recurrence of symptoms compared to teens who did not receive CBT, according to a small, NIMH-funded pilot study published in the December 2008 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.


Studies have found that adults with depression who have responded to medication treatment are less likely to have a relapse if they receive CBT during the follow-up treatment phase, according to researchers Betsy Kennard, Psy.D., of the University of Texas Southwestern Medical Center, and colleagues. Scientists theorize that initial antidepressant treatment may help improve symptoms enough so that a patient becomes more receptive to CBT or other psychosocial component. Kennard and colleagues aimed to determine if a similar sequential treatment strategy would be effective with depressed adolescents.

In this pilot study, 46 depressed youths ages 11 to 18 who had responded to 12 weeks of treatment with the antidepressant fluoxetine (Prozac) were randomly assigned to either six months of continued medication management (MM), or to medication management plus cognitive behavioral therapy (MM+CBT) designed to prevent relapse.

Results of the Study

Kennard and colleagues found that the youths who received only MM were significantly more likely to relapse than the youths who received MM+CBT. The researchers estimated that 37 percent of those in the MM group were likely to relapse, while 15 percent of those in the MM+CBT group were likely to relapse. Patients getting MM+CBT also reported higher rates of satisfaction compared to those getting MM only.


This pilot study demonstrates that, as in adult studies, introducing CBT in follow-up treatment after a patient responds to antidepressant treatment may be a promising strategy in preventing relapse among depressed adolescents.

What’s Next

The researchers currently are conducting a larger trial of MM+CBT to further evaluate the effectiveness of this treatment strategy in youths with depression.

Teens with Treatment-resistant Depression More Likely to Get Better with Switch to Combination Therapy

Teens with difficult-to-treat  depression who do not respond to a first antidepressant medication are more likely to get well if they switch to another antidepressant medication and add psychotherapy rather than just switching to another antidepressant, according to a large, multi-site trial funded by the National Institutes of Health’s National Institute of Mental Health (NIMH). The results of the Treatment of SSRI-resistant Depression in Adolescents (TORDIA) trial were published February 27, 2008, in the Journal of the American Medical Association (JAMA).

“The findings should be encouraging for families with a teen who has been struggling with depression for some time,” said lead researcher David Brent, M.D., of the University of Pittsburgh. “Even if a first attempt at treatment is unsuccessful, persistence will pay off. Being open to trying new evidence-based medications or treatment combinations is likely to result in improvement.”

Adolescents with treatment-resistant depression have unique needs, for which standard treatments do not always work.

“About 40 percent of adolescents with depression do not adequately respond to a first treatment course with an antidepressant medication, and clinicians have no solid guidelines on how to choose subsequent treatments for these patients,” said NIMH Director Thomas R. Insel, M.D. “The results from TORDIA bring us closer to personalizing treatment for teens who have chronic and difficult-to-treat depression.”

Brent and colleagues conducted TORDIA at six regionally dispersed clinics with 334 adolescents ages 12 to 18. The teens in the study all had major depression and had not responded to a previous two-month course of a selective serotonin reuptake inhibitor (SSRI), a type of antidepressant. The teens were randomly assigned to one of four interventions for 12 weeks:

  • Switch to another SSRI—paroxetine (Paxil), citalopram (Celexa) or fluoxetine (Prozac)
  • Switch to a different SSRI plus cognitive behavioral therapy (CBT), a type of psychotherapy that emphasizes problem-solving and behavior change
  • Switch to venlafaxine (Effexor)—another type of antidepressant called a serotonin and norepinephrine reuptake inhibitor (SNRI)
  • Switch to venlafaxine plus CBT
The researchers chose to compare SSRIs with an SNRI because some studies on adults have found that venlafaxine is more effective than an SSRI in managing treatment-resistant depression.

About 55 percent of those who switched to either type of medication and added CBT responded, while 41 percent of those who switched to another medication alone responded. There were no differences in response between those who switched to an SSRI and those who switched to an SNRI, nor were there differences in response among the three SSRIs tested. 

Unlike similar studies on adolescent depression, TORDIA did not exclude teens who were thinking about suicide or had attempted suicide. They were included so that TORDIA would mirror real-world treatment situations, and its findings would be readily applicable to community settings.  

More than half of the participants expressed suicidal thinking and behavior (suicidality) before treatment began, and all teens were monitored weekly for side effects related to suicidality and predictive symptoms like hostility and irritability.   

None of the TORDIA treatment groups, however, showed any measurable effects on suicidality, a finding consistent with other studies that have discovered suicidality does not necessarily subside when the depression does. The researchers reiterated the need for new treatments that specifically prevent or alleviate suicidality.

Although none of the medications seemed to be superior over the others, venlafaxine was associated with more adverse effects, such as skin infections and cardiovascular side effects. The researchers concluded that because venlafaxine had a greater potential for side effects, switching to another SSRI should be considered first.

The findings echo those of the NIMH-funded Treaatment for Adolescents with Depression Study (TADS), which concluded that depressed teens benefited most from a combination of medication and psychotherapy over both the short and long terms. They are also consistent with results from the NIMH-funded Systematic  Treatment Alternatives to Relieve Depression (STAR*D) study, which showed that adults with persistent depression can get well after trying several treatment strategies.

TORDIA was conducted at the University of Pittsburgh, University of Texas at Galveston, University of Texas at Dallas, UCLA, Brown University, and Kaiser Permanente Center for Health Research in Portland, Ore

Maintenance Treatment Crucial for Teens’ Recovery from Depression

Long-term maintenance treatment is likely to sustain improvement and prevent recurrence among adolescents with major depression, according to an NIMH-funded study published in the April 2008 issue of the Archives of General Psychiatry.

The study, led by Paul Rohde, Ph.D., of Oregon Research Institute, analyzed data from theTreatment of  Adolescents with Depression Study (TADS), a large, NIMH-funded trial in which depressed teens were randomized to one of three treatments for 36 weeks—fluoxetine (Prozac), cognitive behavior therapy (CBT) or a combination of both.

Teens with depression, even if they show a good initial response to treatment, are at high risk for relapse and recurrence. However, guidelines for depression maintenance treatment are based on adult needs. Rohde and colleagues aimed to identify whether the available guidelines are appropriate for depressed adolescents.

Among the 242 TADS participants analyzed for this study, 61 percent significantly improved by week 12. The combination group achieved the highest rate of sustained response (71 percent) compared to the fluoxetine-only group (68 percent) and CBT-only group (42 percent).

The majority (82 percent) of teens who reached a sustained positive response by week 12 maintained this level of recovery through week 36. Among those in combination treatment, about 89 percent maintained improvement for the full 36 weeks. Among those in the fluoxetine-only group, 74 percent maintained improvement, but among those in CBT-only treatment, 97 percent maintained their improvement.

The high long-term success rate of CBT suggests that for teens who initially respond to it, CBT may have a preventive effect that helps to sustain positive improvement and potentially avoid relapse or recurrence, even if treatment visits become infrequent, as was the case after the first 12 weeks in the TADS study.

Additionally, the relatively lower sustained success rate for fluoxetine suggests that the effectiveness of fluoxetine therapy may plateau at a certain point for some responders, triggering a need for the addition of psychosocial treatment.

“For those teens who respond to fluoxetine only, adding CBT to their treatment regimen early on would likely increase their chances for continued improvement,” suggested Rohde.

The findings help guide clinicians in deciding on the best maintenance course after a teen responds to an initial treatment. They also emphasize the value of ongoing, long-term treatment, even if treatment visits are infrequent, Rohde and colleagues concluded.


Medication-only Therapy and Combination Therapy Both Cost Effective for Treating Teens with Depression

Treating depressed teenagers with either the antidepressant fluoxetine (Prozac) or a combination of fluoxetine and psychotherapy can be cost effective, according to a recent economic analysis of the NIMH-funded Treatment  for Adolescents with Depression Study (TADS). The study was published online ahead of print April 15, 2008, in the American Journal of Psychiatry.

Marsa Elena Domino, Ph.D., of the University of North Carolina at Chapel Hill, and colleagues compared costs associated with each of the trial’s three active treatment groups—fluoxetine only, cognitive behavioral therapy (CBT) only, and a combination of fluoxetine and CBT—to costs associated with a placebo (sugar pill) group during the first 12 weeks of the trial. The researchers studied direct costs of medication and CBT sessions, and other costs outside the trial, such as visits to primary care providers, school-based services, and lost wages associated with caregivers transporting the adolescent to and from services.

Overall, cost was highest for participants in the combination group—a median of $2,832 per participant. Median cost per participant was $2,287 in the CBT-only group, $942 in the fluoxetine-only group, and $841 in the placebo group. Combination therapy was associated with the highest time and travel costs at $762, but medication costs were lower than those associated with the fluoxetine-only group because those in combination treatment tended to take lower doses of the medication. CBT costs for participants in the CBT-only group and participants receiving it as part of combination treatment did not differ.

Combination treatment cost more, but it also was shown to be more effective than the fluoxetine-only treatment in the first 12 weeks, as reported in August 2004. By assigning a monetary value to clinical improvement, the researchers deduced that both the fluoxetine-only treatment and combination treatment were cost-effective choices.

Finally, CBT was not found to be as effective or as cost effective as the other treatment groups in the first 12 weeks of the trial. However, by the end of the 36-week study, response rates in the CBT-only group had essentially caught up with the other two groups. Therefore, the researchers predicted that if long-term costs remain stable, CBT-only may become a cost-effective treatment choice as well.


Preventive Treatment May Help Head Off Depression Following a Stroke

For the first time, researchers show that preventive treatment with an antidepressant medication or talk therapy can significantly reduce the risk or delay the start of depression following an acute stroke, according to a study funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. These findings differ from past studies attempting to prevent poststroke depression. The study appears in the May 28, 2008, issue of the Journal of the American Medical Association.

“Post stroke depression can impede rehabilitation and recovery of functional skills, reduce quality of life, and may also shorten a person’s lifespan,” notes NIMH Director Thomas R. Insel, MD. “Thus, early detection and intervention, in addition to preventive methods, are important components of post stroke treatment.”

Robert G. Robinson, M.D., of the University of Iowa, and colleagues compared the effects of the antidepressant medication escitalopram (Lexapro) with placebo (sugar pill) in 117 adults, ages 50-90, who had suffered an acute stroke within the previous three months. Neither the participants nor the researchers knew who was receiving the medication or a placebo during the study. Another group of 59 adults were randomly selected to receive Problem Solving Therapy (PST), a talk therapy that helps people identify problems that interfere with daily living and contribute to depressive symptoms and then develop strategies to solve those problems. None of the participants had depression at the start of the study.

The researchers tested escitalopram because previous research had shown that it worked quickly and effectively and could be tolerated over the 12-month study period. They chose PST over other forms of talk therapy because it was developed for use in older people.

People who received either escitalopram or PST were less likely to develop depression (8.5 percent and 11.9 percent, respectively) than those who received the placebo (22.4 percent). 

This is the first study of its kind to show some cases of post stroke depression can be prevented with intervention. In addition to the need for further studies, greater attention needs to be given to improving the early detection of and interventions for depression during standard stroke care, the researchers say.


Asarnow JR, Emslie G, Clarke G, Wagner KD, Spirito A, Vitiello B, Iyengar S, Shamseddeen W, Ritz L, Birmaher B, Ryan N, Kennard B, Mayes T, DeBar L, McCracken J, Strober M, Suddath R, Leonard H, Porta G, Keller M, Brent D. Treatment of SSRI-resistant depression in adolescents: predictors and moderators of treatment response. Journal of the American Academy of Child and Adolescent Psychiatry. Published online ahead of print February 4, 2009.

Brent D, et al. The treatment of adolescents with SSRI-resistant depression (TORDIA): A comparison of switch to venlafaxine or to another SSRI, with or without additional cognitive behavioral therapy. Journal of the American Medical Association. 2008 Feb 27.

Brent D, Emslie G, Clark G, Wagner KD, Asarnow JR, Spirito A, Ritz L, Vitiello B, Iyengar S, Birmaher B, Ryan N, Zelazny J, Onorato M, Kennard B, Mayes T, DeBar L, McCracken J, Strober M, Suddath R, Leonard H, Porta G, Keller M. Predictors of spontaneous and systematically assessed suicidal adverse events in the Treatment of SSRI-resistant Depression in Adolescents (TORDIA) study. American Journal of Psychiatry. Online ahead of print February 16, 2009.

Domino ME, Burns BJ, Silva SG, Kratochvil CJ, Vitiello B, Reinecke MA, Mario J, March JS. Cost-effectiveness of treatments for adolescent depression: results from TADS. American Journal of Psychiatry. Published online ahead of print April 15, 2008.

Du J, Wang Y, Hunter R, Wei Y, Blumenthal R, Falke C, Khairova R, Zhou R, Yuan P, Machado-Vieira R, McEwen B, Manji HK. Dynamic regulation of mitochondrial functions by glucocorticoids. Proc Natl Acad Sci USA. 2009 Feb 2.

Fava M, et al. Difference in treatment outcome in patients with anxious versus nonanxious depression: A STAR*D Reprot. American Journal of Psychiatry. Published online ahead of print January 2, 2008.

Hasler G, Fromm S, Carlson PJ, Luckenbaugh DA, Waldeck T, Geraci M, Rosier JP, Neumeister A, Meyers N, Charney DS, Drevets WC. Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. Arch Gen Psychiatry. 2008 May;65(5):521-31.PMID: 18458204

B, et al. Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2008 Dec; 47(12):1395-1404

Merikangas KR. Ames M, Cui L, Stang PE, Ustun TB, von Korff M, Kessler, RC. The impact of comorbidity of mental and physical conditions on role disability in the US adult population. Archives of General Psychiatry, Oct 2007; VOL 64(10).

Peterson BS, Warner V, Bansal R, Zhu H, Hao X, Liu J, Durkin K, Adams PB, Wickramaratne P, Weissman MM.Cortical thinning in persons at increased familial risk for major  depression. Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6273-8. PMID: 19329490

Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR.  Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression.  Molecular Psychiatry, online March 12, 2008.

Robinson RG, Jorge RE, Moser DJ, Acion L, Solodkin A, Small SL, Fonzetti P, Hegel M, Arndt S. Escitalopram and problem solving therapy for prevention of poststroke depression: A randomized trial. JAMA. 2008 May 28;299(20):2391-2400

Rohde P, Silva SG, Tonev ST, Kennard BD, Vitiello B, Kratochvil CJ, Reinecke MA, Curry JF, Simons AD, March JS. Achievement and maintenance of sustained improvement during TADS continuation and maintenance therapy. Archives of General Psychiatry. 2008 Apr; 65(4): 447-455.

Rosier JP, Levy J, Fromm SJ, Wang H, Hasler G, Sahakian BJ, Drevets WC. The Effect of Acute Tryptophan Depletion on the Neural Correlates of Emotional Processing in Healthy Volunteers.Neuropsychopharmacology. 2007 Sep 19; [Epub ahead of print] PMID: 17882232

Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg A, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Fava M. Acute and Longer-term Outcomes in Depressed Outpatients Who Required One or Several Treatment Steps: A STAR*D Report.  American Journal of Psychiatry. 2006 Oct; 163(11):

Sharot T, Riccardi AM. Raio CM, Phelps EA. Neural mechanisms mediating optimism bias. Nature. 2007 Oct 24; [Epub ahead of print] PMID: 17960136

Wisner KL, Sit DKY, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Jones-Ivy S, Bodnar LM, Singer LT. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. American Journal of Psychiatry. Online ahead of print March 15, 2009.

Home |FAQs |Accreditations |Contact Us |Login |Privacy Policy |Course Catalog | Site Map | Create Account