Seeking understanding of collective traumas helps adjustment process

According to new research by John Updegraff, a Kent State University professor and colleagues from the University of California at Irvine, individuals who are able to quickly make sense of collective traumas such as the 9/11 terrorist attacks cope better in the long run.

The study, which appears in the September issue of Journal of Personality and Social Psychology, suggests that finding meaning in the immediate aftermath of the attacks was an important coping response that helped many Americans adjust by reducing their fears of future terrorism.

Dr Updegraff, an assistant professor of psychology, used a large national sample to examine Americans' responses to the terrorist attacks of 9/11, beginning immediately after the event and continuing for the following two years. Two months following the attacks, respondents were asked about whether they were able to make sense of the attacks.

"Most Americans were trying to find a way to explain why the attacks occurred, but less than half were successful in doing so," says Updegraff. Explanations ranged from blaming the events on either the terrorists or on American foreign policy, focusing on positive consequences of the attacks such as patriotism or greater appreciation of social ties, or interpreting the events in a historical or religious context.

"Regardless of how people explained the events, those who came to some personal understanding of why the attacks occurred fared better over time than those who were unable to," Updegraff says. "They were less plagued by fears of future terrorism and less distressed by the attacks over the following two years."

These findings support the idea that being able to make sense of traumatic events helps people adjust. However, most previous studies have focused on direct personal trauma such as bereavement. This is the first study to find that meaning facilitates adjustment for individuals indirectly exposed to large-scale collective traumas such as terrorist attacks, school shootings, or natural disasters.

---

Updegraff JA, Silver RC, Holman EA. Searching for and Finding Meaning in Collective Trauma: Results From a National Longitudinal Study of the 9/11 Terrorist Attacks. J Pers Soc Psychol. 2008 Sep;95(3):709-22.   [Abstract | Full text ()]

A sudden and dramatic increase in pediatric suicides may reflect an emerging trend rather than a single-year anomaly. That's the conclusion of new research which looked at pediatric suicide trends over a 10-year period, conducted at The Research Institute at Nationwide Children's Hospital and published in the September 3rd issue of the Journal of the American Medical Association (JAMA).

Following more than a decade of steady decline, the suicide rate among U.S. youth younger than 20 years of age increased by 18 percent from 2003-2004 - the largest single-year change in the pediatric suicide rate over the past 15 years. Although worrisome, the one-year spike observed in 2003-2004 did not necessarily reflect a changing trend. So researchers have been waiting to examine national youth suicide data from 2005 in order to determine whether the increase persisted from 2004-2005, and it don't look promising.

"Suddenly in 2004 we see the sharpest increase in the past 15 years and it appears that it's persisting into 2005," says the study's lead author, Jeff Bridge, PhD, a principal investigator in The Research Institute at Nationwide Children's Hospital.

The researchers estimated the trend in suicide rates from 1996-2003 using log-linear regression. Using that trend line, they estimated the expected suicide rates in 2004 and 2005 and compared the expected number of deaths to the actual observed number of deaths. Researchers found that although the overall observed rate of suicide among 10 to 19 year olds decreased by about 5 percent between 2004 and 2005 (the year following the initial spike) both the 2004 and 2005 rates were still significantly greater than the expected rates, based on the 1996-2003 trend.

"The fact that this significant increase in pediatric suicides continued into 2005 implies that the alarming spike witnessed from 2003-2004 was more than just a single-year anomaly," said Dr Bridge. "We now need to consider the possibility that the increase is an indicator of an emerging public health crisis."

In order to understand the possible causes behind the increase researchers say additional studies must be conducted.

One answer may lie in the prescription of antidepressant medication. Because of concerns over possible increases in suicidal behaviors linked to the drugs, the number of kids prescribed antidepressants has dropped by as much as 20 percent according to John Campo, MD, Chief of Child & Adolescent Psychiatry at Nationwide Children's Hospital, and this may be having a dire impact.

"The vast majority of young people who complete suicide have some sort of psychiatric disorder. Most commonly depression or some mood disorder," Dr Campo.

So the kids who need the medicine most may not be getting it. Campo says there is no proven link between the drop in prescriptions and the rise in suicides, but the fact that they happened at the same time is worth further investigation.

Other factors that should be considered as possible contributors include the influence of internet social networks and increases in suicide among U.S. troops.

Researchers stress that, whatever the explanation, effective interventions to reduce pediatric suicides must be addressed nationally.

---

Bridge JA, Greenhouse JB, Weldon AH, Campo JV, Kelleher KJ. Suicide Trends Among Youths Aged 10 to 19 Years in the United States, 1996-2005. JAMA. 2008;300(9):1025-1026.   [Extract]

Brain scans taken at different times of year suggest that the actions of the serotonin transporter-involved in regulating the mood-altering neurotransmitter serotonin-vary by season, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals. These fluctuations may potentially explain seasonal affective disorder and related mood changes.

"It is a common experience in temperate zones that individuals feel happier and more energetic on bright and sunny days and many experience a decline in mood and energy during the dark winter season," the authors write as background information in the article. This is thought to be related to variations in brain levels of serotonin, which is involved in the regulation of functions such as mating, feeding, energy balance and sleep. The serotonin transporter, a protein that binds to serotonin and clears it from the spaces between brain cells, "is a key element in regulating intensity and spread of the serotonin signal."

Nicole Praschak-Rieder, MD, and Matthaeus Willeit, MD, of the Centre for Addiction and Mental Health and the University of Toronto, Ontario, Canada, and colleagues studied 88 healthy individuals (average age 33) between 1999 and 2003. Participants underwent one positron emission tomography (PET) scan to assess serotonin transporter binding potential value, an index of serotonin transporter density. The higher the binding potential value, the less serotonin circulates in the brain. For the analysis, individual scans were grouped according to the season of the scan-fall and winter or spring and summer.

"Serotonin transporter binding potential values were significantly higher in all investigated brain regions in individuals investigated in the fall and winter compared with those investigated in the spring and summer," the authors write. When they matched binding potential values to meteorological data, the researchers found that higher values occurred during times when there were fewer hours of sunlight per day.

"An implication of greater serotonin transporter binding in winter is that this may facilitate extracellular serotonin loss during winter, leading to lower mood," the authors write. "Higher regional serotonin transporter binding potential values in fall and winter may explain hyposerotonergic [related to low serotonin levels] symptoms, such as lack of energy, fatigue, overeating and increased duration of sleep during the dark season."

"These findings have important implications for understanding seasonal mood change in healthy individuals, vulnerability to seasonal affective disorder and the relationship of light exposure to mood," they conclude. "This offers a possible explanation for the regular reoccurrence of depressive episodes in fall and winter in some vulnerable individuals."

The study was supported by grants from the National Alliance for Research on Schizophrenia and Depression, the Austrian Science Foundation, the Canadian Institute for Health Research, the Ontario Mental Health Foundation, the Canada Foundation for Innovation and the Ontario Innovation Trust.

---

Praschak-Rieder N, Willeit M, Wilson AA, et al. Seasonal Variation in Human Brain Serotonin Transporter Binding. Arch Gen Psychiatry. 2008;65(9):1072-1078.   [Abstract]

Low-birth-weight babies appear to be at higher risk for psychiatric disturbances from childhood through high school than normal-birth-weight children, according to a report in the September issue of Archives of General Psychiatry. In addition, low-birth-weight children from urban communities may be more likely to have attention problems than suburban low-birth-weight children.

Advances in neonatal medicine have raised the survivorship of low-birth-weight infants (2,500 grams/5.5 pounds or less), especially very low-birth-weight infants (1,500 grams/3.3 pounds or less) and extremely low-birth-weight infants (1,000 grams/2.2 pounds or less), according to background information in the article. Previous studies have reported that low-birth-weight children appear to have an increased risk of internalizing, externalizing and attention problems.

Kipling M. Bohnert, B.A., and Naomi Breslau, PhD, of Michigan State University, East Lansing, examined the long-term association between low-birth-weight and psychiatric problems among 413 children from a socially disadvantaged community in Detroit and 410 children from a middle-class Detroit suburb. Children's psychiatric disturbances were rated by mothers and teachers at ages 6, 11 and 17.

Psychiatric disturbances were separated into three categories: externalizing, including delinquent and aggressive behavior; internalizing, including withdrawn behavior and anxiety/depression; and attention, including characteristic symptoms of ADHD such as not being able to pay attention for long or difficulty following directions.

Low-birth-weight children were more likely to exhibit externalizing and internalizing problems than normal-birth-weight children in their community. "An increased risk of attention problems was associated with low birth weight only in the urban community and was greater among very low-birth-weight children (weighing 1,500 grams or less) than heavier low-birth-weight children (weighing 1,501 grams to 2,500 grams)," the authors write. "In the suburban community, there was no increased risk for attention problems associated with low birth weight. Psychiatric outcomes of low birth weight did not vary across ages of assessments."

"Attention problems at the start of schooling predict lower academic achievement later, controlling for key factors that contribute to academic test scores, which in turn predicts termination of schooling and curtailed educational attainment," the authors conclude. "Attention problems influence academic performance by reducing the time that students devote to class learning and homework assignments and hinder organization and work habits.

"Early interventions to improve attention skills in urban low-birth-weight children might yield better outcomes later."

The study was supported by grants from the National Institute of Mental Health and from the National Institute on Drug Abuse.

---

Bohnert KM, Breslau N. Stability of Psychiatric Outcomes of Low Birth Weight. Arch Gen Psychiatry. 2008;65(9):1080-1086.   [Abstract]

Professor Dr Eberhard Fuchs,
Clinical Neurobiology Laboratory, German Primate Center, Goettingen,
and Department of Neurology, University Medical Center,
Georg-August-University Goettingen, Germany

Presented at the 21st Congress of the European College of Neuropsychopharmacology 2008, Barcelona, Spain

The brain is the key organ in the response to stress. It reacts in a complex, orchestrated manner that is related to the activation and inhibition of neural structures involved in sensory, motor, autonomic, cognitive and emotional processes. It is the brain which finally determines what in the world is threatening and might be stressful for us, and which regulates the stress responses that can be either adaptive or maladaptive.

Chronic stress can affect the brain and lead into depression: Environmental stressors (e.g. job and family situation, neighborhood) and especially stressful life events such as trauma or abuse are amongst the most potent factors to induce depression. Since the development of novel approaches to antidepressant treatment is based upon an improved neurobiological understanding of this condition, new information about the cellular changes that take place in the brain is required.

Depression is a chronic, recurring, multifactorial, and life-threatening disorder, which represents a collection of psychological, neuroendocrine, physiological and behavioral symptoms. Chronicity and frequency of these symptoms constitute the clinical condition. Depressive disorders affect up to 20% of people at some time in their life. In primary care, an estimated 20 percent of patients suffer from depression, but often are not diagnosed correctly [1].

Depressive disorders are among the most prevalent illnesses worldwide, producing significant public health and socioeconomic problems [3]. The immense costs of depression account for approximately 1% of the gross domestic product in Europe (approximately 100 billion Euro). Depression is affecting more than 120 million people globally, and is set to rise to become one of the leading causes of disability, second only to cardiovascular disease, by the year 2015.

The areas of the brain that are most affected by the changes caused by depression are the prefrontal cortex, amygdala and hippocampus, which are central to emotion, memory and learning. Structural and functional changes as a consequence of stress and/or major depression are a reduction in volume, neuronal size and density, associated with changes in cerebral blood flow and glucose metabolism. In addition, there is a reduced density of glial support cells that are instrumental in the communication between nerve cells, which is particularly relevant to the reduced volume of the prefrontal cortex and the hippocampus. The shrinkage might explain some of the emotional changes observed in people with depression.

The 'stress hypothesis' of affective disorders has stimulated the development of putative animal models of depression. Animal models today are generally regarded as invaluable in preclinical research on human psychopathology, and are thus of prime interest in studying the pathophysiology of depression and specific responses to antidepressant drug treatments.

The discovery that the adult nervous system is capable of replacing its cells has attracted considerable interest in the scientific community. Up to then, neural networks in adults have been thought to be fixed and immutable, without the potential to regenerate: This assumption was prominently pronounced by the famous Spanish neuroscientist Santiago Ramon y Cajal, who postulated that "everything may die, nothing may regenerate" [5].

Current research has overturned this view and has shown that the formation of new nerve cells (neurogenesis) also takes place in the adult brain.

Neurogenesis can be modified by positive modulators such as learning, physical exercise, and hormonal influence, as well as negative modulators such as acute and chronic stress.

While stress has been found to inhibit adult neurogenesis in the hippocampus - a brain area that is central to emotion, memory and learning - antidepressant treatment has the opposite effect. Moreover, patients with mood disorders often have reduced hippocampal volumes. This evidence rapidly led to the formulation of the 'neurogenesis hypothesis' of depression, which says that adult neurogenesis in the hippocampus is a candidate substrate for both the etiology and the treatment of major depressive disorders. However, according to the current view, newborn cells in the hippocampus per se may not be critical for the development of depression, but may be required for certain behavioral effects of antidepressants [4].

There is increasing evidence that in addition to neurogenesis, stress and antidepressant treatment also induce changes in the formation of specific glial support cells (gliogenesis) that are critical for the survival of the neurons in the brain.

There are about 100 times more glial cells than nerve cells, providing energy and nutrition to the neurons. Besides their 'housekeeping' functions, glial cells are instrumental to neural communication and regarded as dynamic regulators of synaptic strength and synapse formation. They also possess receptors for neurotransmitters and steroid hormones that, similarly to receptors of neurons, can trigger electrical and biochemical events in the cell. Therefore, structural changes of glial cells are likely to have an important functional significance for the communication between neurons and between neurons and glial cells.

In the adult brain various antidepressant treatment strategies can not only stimulate neurogenesis, but also exert similar stimulatory effects on gliogenesis. Moreover, animal studies have recently shown that chronic stress inhibits cell proliferation not only in the hippocampus but also in the prefrontal cortex, and that this inhibitory effect can be counteracted by antidepressant treatment [6].

The significance of these observations is strengthened by in vivo neuroimaging studies in patients with mood disorders that consistently point to the involvement of prefrontal brain sites in the pathophysiology of the disease. These imaging findings are further supported by reports on human post-mortem tissues revealing that the number of glial cells in the prefrontal cortex is adversely affected in patients with mood disorders.

Experiments show that stress and depression inhibit the growth of new nerve cells as well as glial support cells, and that this inhibitory effect can be counteracted by antidepressive therapy.

Clinical implications

• Within the last two decades, the understanding of the mature brain has changed: Neuronal and glial cell networks in the brain are far from being fixed and immutable - a multitude of factors such as environmental stimulation, learning, growth factors, glucocorticoids, sexual hormones, stress, aging, and several neurotransmitters regulate the generation of new neurons. Antidepressants stimulate the growth of neurons and glial cells again so the brain changes that occur as a consequence of stress and depression are generally reversible.


• Today it is widely believed that neurogenesis in the adult brain is restricted to selected brain regions such as zones of the hippocampus and the lateral brain ventricles. However, a growing number of recent studies describe the generation of new neurons also in the adult neocortex. Although small in both number and size, these new cells could have a significant impact on neocortical function.


• Interrelation between psychiatric diseases and adult neocortical cytogenesis is suggested by preclinical studies of stress (inhibiting cytogenesis) and antidepressive treatment (stimulating cytogenesis), but so far the existence of a causative relationship remains speculative. Nevertheless these findings should encourage further studies on neocortical cytogenesis and its function in affective disorders such as depression, which may provide additional evidence that impairments of brain neuroplasticity are important features of depressive disorders.


• On the basis of this research it might be possible to develop new strategies for more effective therapies of depressive diseases.

These discoveries show that brain cells can be adversely affected by stress and depression which may lead to a new approach to antidepressant treatment.

References:

1. Wittchen HU, Höfler M, Meister W. Depressionen in der Allgemeinpraxis. Die bundesweite Depressionsstudie. Stuttgart: Schattauer, 2000
2. Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 2007;370:851-858 [Abstract]
3. World Health Organisation (WHO). The World Health Report 2001. Mental Health: New Understanding, New Hope. [Full text (, 2.45MB)]
4. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nature Neuroscience 2007;10:1110-1115 [Abstract]
5. Ramón y Cajal, SR. Degeneration and regeneration of the nervous system. London, Oxford University Press, 1928
6. Czéh B, Müller-Keuker JIH, Rygula R, et al. Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment. Neuropsychopharmacology 2007;32:1490-1503 [Full text]

Researchers at UT Southwestern Medical Center have discovered in mice that the brain must create new nerve cells for either exercise or antidepressants to reduce depression-like behavior.

In addition, the researchers found that antidepressants and exercise use the same biochemical pathway to exert their effects.

These results might help explain some unknown mechanisms of antidepressants and provide a new direction for developing drugs to treat depression, said Dr Luis Parada, chairman of developmental biology and senior author of a study in the Aug. 14 issue of the journal Neuron.

In animals, it was already known that long-term treatment with antidepressants causes new nerve cells to be generated in the dentate gyrus, a part of the hippocampus. Exercise, which can also relieve the symptoms of depression, stimulates the generation of new nerve cells in the same area.

"We would never claim that what we study in mice directly relates to how antidepressants work in humans, but there are interesting features in parallel," Dr Parada said. "The study unifies different observations that point to the brain's dentate gyrus region and to creation of nerve cells as being important in depression."

Antidepressants act very quickly to increase levels of neurotransmitters which nerve cells use to communicate. It takes several weeks to several months, however, for the patients who respond to such treatments to feel less depressed. Dr Parada said this implies that some other long-term mechanism is also at work.

The current study was designed to test several phenomena that have long been observed in animal studies but have not been studied together to see if they are linked.

The researchers focused on a molecule called TrkB, or Track-B, which is found on the surface of nerve cells and responds to several growth factors to cause new nerves to grow in the dentate gyrus.

They genetically engineered mice to lack TrkB specifically in the stem cells that give rise to new neurons, then gave them antidepressants for several weeks or allowed them to run on wheels. When the mice were tested for depressive behavior, the tests revealed that neither the antidepressants nor the exercise had helped them, and the animals also had not grown new nerve cells in the dentate gyrus.

"At least in mice, this result directly links antidepressants and voluntary exercise with TrkB-mediated creation of nerve cells," Dr Parada said.

The results also showed that antidepressants required TrkB to stimulate the growth of new nerve cells.

Matching the timeframe for medicated patients to feel less depressed, it takes several weeks for new nerve cells to grow, Dr Parada said. This parallel effect, he said, may mean that antidepressants need to stimulate growth of new cells in the dentate gyrus in order to achieve their full effect.

"We can get biochemical, physiological, behavioral and anatomical results in animal models," Dr Parada said. "These all resonate with the human condition, so perhaps you have a physiological relevancy.

"There could be a way to stimulate growth of nerve cells to fight depression, for example."

The work was supported by the National Institute of Neurological Disorders and Stroke.

---

Yun Li, Bryan W. Luikart, Shari Birnbaum, et al. TrkB Regulates Hippocampal Neurogenesis and Governs Sensitivity to Antidepressive Treatment. Neuron 2008 Aug 14;59:399-412.  

[Abstract]

Professor Erkki T. Isometsä, MD, Ph.D.
Institute of Clinical Medicine, Department of Psychiatry,
University of Helsinki, Finland

Antidepressants are the cornerstone of treatment of depressive disorders in health care. Their efficacy in treating depression is undisputable, although it leaves room for improvement.

However, recent reports also suggest that antidepressants might, in some rare cases, actually worsen suicidal tendencies instead of alleviating them. As a consequence, research has intensified to clarify this issue, and regulatory authorities in many countries have reconsidered their cost-benefit ratio.

While there is no doubt that such potential side-effects of antidepressant therapy are a very serious issue, it is important to obtain a balanced view of all the clinical and epidemiological facts pertaining the effect of antidepressant therapy in relation to suicidal behavior.

Suicide is a significant public health issue. The World Health Organization (WHO) estimates that annually about one million people worldwide complete suicide. Thus, worldwide significantly more people die by suicide than e.g. in armed conflicts or as victims of terror, or tragic natural disasters such as earthquakes. Furthermore, completed suicides represent only a tip of the iceberg of suicidal behavior as for every completed suicide there is more than ten-fold number of non-fatal suicide attempts. Worldwide nearly ten percent of individuals report having had suicidal ideation over their lifetime (Bernal M, et al, 2007; Nock MK, et al, 2008).

In numerous psychological autopsy studies conducted worldwide, more than 90 percent of those completing suicide were shown to have suffered from mental disorders. Suicides have multiple causes and should therefore not be seen as merely consequences of mental disorders. Nevertheless, for health care, the strong relationship between mental disorders and suicides involves an obligation for prevention.

Mood disorders, principally major depression and bipolar disorder, are associated with about 60% of completed suicides (Mann JJ, et al, 2005). More than half of the subjects completing suicide during major depression communicate their intent during the final 3 months, and almost all patients attempting suicide report suicidal ideation (Isometsä ET, et al, 1994; Sokero TP, et al, 2003). This communication of intent allows prevention by appropriate treatment and other measures. However, the problem faced by psychiatrists is a high number of suicidal patients and the difficulty of identifying those at highest risk of completion among them.

Among psychiatric patients with major depression, non-fatal suicidal behavior is remarkably common. About 40 percent have attempted suicide, and from 47 percent to 69 percent will have experienced suicidal ideation (Sokero TP, et al, 2003); Malone KM, et al, 1995) when depressed.

The risk for suicide attempts is closely intertwined with the commonly recurrent course of depression; the risk is about eightfold during a major depressive episode compared to periods of full remission (Sokero TP, et al, 2005). The more time a patient spends in a depressed state, the higher is the risk of suicidal acts over time. Among depressed patients having suicidal ideation, decline in suicidal ideation is predicted by declines in the levels of both depressive symptoms as well as hopelessness (Sokero P, et al, 2006).

Thus, reducing the severity and the duration of a depressed state by antidepressant treatment is likely to be an effective preventive measure for suicidal acts, and alleviation of depression and hopelessness can be reasonably expected to result in disappearance of suicidal thoughts.

Depression is present in more than half of suicides, but in the majority of these suicides it has remained untreated at time of death (Isometsä ET, et al, 1994; Henriksson S, et al, 2001). Even after a suicide attempt, depression often remains unrecognized, untreated or undertreated (Oquendo MA, et al, 2002).

The role of targeting depression for suicide prevention has been highlighted in a worldwide review and consensus of leading authorities in suicide research, in which the effectiveness of specific suicide-preventive interventions was examined: Only physician education in recognition and treatment of depression as well as restricting access to lethal means were clearly identified to prevent suicide, other interventions still need more testing (Mann JJ, et al, 2005). Thus, treating mood disorders and other psychiatric disorders is a central component of suicide prevention.

Improved recognition and treatment of depressed patients in primary care alongside improved access to psychiatric services is a key prevention strategy for suicide.

Antidepressants and suicide risk: what is the evidence?

In numerous short-term randomized clinical trials (RCTs) of antidepressants for depression in children and adolescents (<19 years), antidepressants are found to be associated with a slightly higher proportion (0.7%) of patients reporting suicidal ideation or a suicide attempt than control patients receiving placebo (Bridge JA, et al, 2007). It is important to note that there are no completed suicides in any of these studies.

Adults treated with SSRI antidepressants in randomized clinical trials have a similar risk of either non-fatal self harm or suicidal thoughts than those on placebo (Gunnell D, et al, 2005 & update 2006).

It is undisputable that at least among children and adolescents, antidepressants have some potential of causing harm to a small subgroup of vulnerable patients, at least in the beginning of treatment. However, there are several reasons why such trials are likely to create a distorted view of the total balance of benefits and harms of antidepressants:

• Short-term clinical trials are designed to produce statistical evidence of efficacy for regulatory purposes, and their duration is only as long as necessary to produce this evidence. Thus, the trial ends when the drug response has evolved. During the trial patients spend most of their weeks with possible side effects, but not yet full antidepressant response. With regard to suicidal behavior, the benefits come with the response, gradually over time.


• For ethical reasons, subjects who are severely suicidal at the time of evaluation for the trial must be excluded, since they might receive placebo. This changes the balance between observed negative and positive effects with regard to suicidal behavior in these trials.
  
  Worsening of mild pre-existing or newly emerging suicidal behavior can be usually detected. However, as most severely suicidal patients must be excluded before a trial starts, it remains unknown whether they would benefit from the active treatment. As naturalistic studies do suggest such improvement, this bias is not merely hypothetical.
  
  Antidepressant trials have not been designed to investigate suicidal behavior, and they cannot provide unbiased information on their overall effects related to it.


• Factors resulting in short-term suicidal ideation, or even less severe suicide attempts do not necessarily result in significantly increased risk for completed suicide, as mental disorders and their symptoms related to completed suicides are usually more severe. There is no evidence of increased rates completed suicides in antidepressant trials (Khan A, et al, 2003).


• Clinical trials do not reflect usual treatment. In usual care, the attending doctor can promptly discontinue antidepressants that involve intolerable side-effects, adjust dosage, and switch and combine agents. Antidepressants are only part of treatment, which should always include a trustful relationship between the doctor and the patient, with necessary support and psychosocial treatments.

The most important test for the role of antidepressants in suicide prevention is real life. In contrast to these randomized clinical trials, observational studies of antidepressant treatment, which typically include abundantly highly suicidal patients, demonstrate a marked alleviation of suicidal behavior in the vast majority of patients.

In clinical practice, the benefits of treatment are seen over time as the drug response consolidates. Patient population studies of adolescents report lower rates of suicide attempts and of adults both attempts and completions over time as treatment continues (Valuck RJ, et al, 2004; Jick H, et al, 2004; Simon G, et al, 2007; Sokero P, et al, 2006; Simon G, et al, 2006).

In many western countries (e.g. Korkeila et al, 2007), increasing use of antidepressants on the national and regional level expectedly correlates with declining suicide mortality. Of course, such ecological studies do not prove that antidepressants have caused the observed decline in suicides, but nevertheless, they are consistent with a positive or at worst, neutral net effect on suicides. Most importantly, there is no evidence for increased national suicide rates due to increased use of antidepressants.

Antidepressants reduce the severity, and the time a patient spends in a depressive state, which are credible factors in reducing the risk for suicidal acts.

Clinical implications

• Depression is the most important single factor predisposing to suicide, and more than half of all subjects completing suicide are known to have suffered from depression. Thus, any treatment that is widely available, safe and efficacious in alleviating depression is plausible for purposes of suicide prevention.


• Register-based and observational studies have provided individual-level information on depressed subjects on and off antidepressants in real life conditions: Compared to randomized clinical trials these studies give a more realistic account of risk of suicidal behavior, and suggest antidepressants to be beneficial for suicide prevention.


• While antidepressants likely have a potential for provoking suicidal behavior in some vulnerable individuals in the early phases of treatment, from a public health perspective, the epidemiologically much more important effect of antidepressants is to alleviate depression and thus reduce the risk of suicide.

References:

• Bernal M, Haro JM, Bernert S, et al, ESEMED/ MHEDEA Investigators. Risk factors for suicidality in Europe: results from the ESEMED study. J Affect Disord. 2007;101:27-34 [Abstract]
• Nock MK, Borges G, Bromet EJ, et al, Cross-national prevalence and risk factors for suicidal ideation, plans and attempts. Br J Psychiatry. 2008;192:98-105 [Abstract]
• Mann JJ, Apter A, Bertolote J, et al, Suicide prevention strategies. A systematic review. JAMA 2005;294:2064-2074 [Full text]
• Isometsä ET, Henriksson MM, Aro HM, et al, Suicide in major depression. Am J Psychiatry 1994;151:530-536 [Abstract]
• Sokero TP, Melartin TK, Rytsälä HJ, et al, Suicidal ideation and attempts among psychiatric patients with major depressive disorders. J Clin Psychiatry 2003;64:1094-1100 [Abstract]
• Malone KM, Haas GL, Sweeney JA, et al, Major depression and the risk of attempted suicide. Journal of Affective Disorders 1995;34:173-185 [Abstract]
• Sokero TP, Melartin TK, Rytsälä HJ, et al, Prospective study of risk factors for attempted suicide among patients with DSM-IV major depressive disorder. Br J Psychiatry 2005;186:314-318 [Full text]
• Sokero P, Eerola M, Rytsälä H, et al, Decline in suicidal ideation among patients with MDD is preceded by decline in depression and hopelessness. Journal of Affective Disorders 2006;95:95-102 [Abstract]
• Henriksson S, Boethius G, Isacsson G. Suicides are seldom prescribed antidepressants: findings from a prospective prescription database in Jamtland county, Sweden, 1985-95. Acta Psychiatr Scand 2001;103:301-306 [Abstract]
• Oquendo MA, Kamali M, Ellis SP, et al, Adequacy of antidepressant treatment after discharge and the occurrence of suicidal acts in major depression: a prospective study. Am J Psychiatry 2002;159:1746-1751 [Full text]
• Bridge JA, Iyengar S, Salary CB, et al, Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. A meta-analysis of randomized controlled trials. JAMA 2007;297:1683-1696. [Full text]
• Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo-controlled, randomised controlled trials submitted to the MHRS's safety review. BMJ 2005;330:385-8 [Full text]
  (updated in BMJ 2006;332:1453) [Full text]
• Khan A, Khan S, Kolts R et al, Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: Analysis of FDA reports. Am J Psychiatry 2003;160:790-792 [Full text]
• Valuck RJ, Libby AM, Sills MR, et al, Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs 2004;18:1119-1132 [Full text]
• Jick H, Kaye J, Jick S. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292:338-43 [Full text]
• Simon G, Savarino J. Suicide attempts among patients starting depression treatment with medications and psychotherapy. Am J Psychiatry 2007:164:1029-1034. [Full text]
• Simon G, Savarino J, Operkalski B, et al, Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163:41-47. [Full text]
• Korkeila J, Salminen JK, Hiekkanen H, et al, Use of antidepressants and suicide rate in Finland: an ecological study. J Clin Psychiatry. 2007;68:505-11. [Abstract]

Depressed women are 33 percent more likely than men to have full remission with SSRI antidepressants, suggesting a biological basis for difference in response

Women with depression may be much more likely than men to get relief from the commonly used, inexpensive Selective Serotonin Re-uptake Inhibitor (SSRI) class antidepressant drug citalopram (Celexa^®), a new study finds. But many members of both sexes may find that it helps ease their depression symptoms.

The persistence of a gender difference in response to the drug - even after the researchers accounted for many complicating factors - suggests that there is a real biological difference in the way the medication affects women compared with men. The reasons for that difference are still unclear, but further studies are now examining hormonal variations that may play a role.

Researchers from the University of Michigan Depression Center and their colleagues from around the country tested the drug's ability to help depression patients achieve remission, or total relief from their symptoms, in a multi-year study called STAR*D.

The gender differences emerged from a detailed analysis of data from 2,876 men and women who had a clear diagnosis of major depression, and took citalopram over a number of weeks, with the doses increasing over time.

In the end, women were 33 percent more likely to achieve a full remission of their depression, despite the fact that the women were more severely depressed than the men when the study began.

The study showed no differences between men and women in side effects, the amount of time that patients stuck to taking the drug, or the amount of time it took for them to achieve remission of their symptoms.

"Other studies have suggested that there are differences between men and women in response to different antidepressants, but the evidence has been conflicting," said the study's lead author, Elizabeth Young, MD, a professor of psychiatry at the University of Michigan Medical School and a Depression Center member. "This study is large enough, and we were able to control for enough complicating factors, that we feel confident there is a true difference. These results have clear implications for the clinical treatment of depression."

Young and her colleagues conducted the analysis of data from men and women between the ages of 18 and 75 who were being treated by either primary care physicians or psychiatrists. All of the patients had been experiencing depression for years, with the average length of illness around 12 years.

In earlier decades gender differences had been seen in studies of patients taking tricyclic antidepressants, an older generation of drugs, with men tending to respond better to these medications. But for more than 15 years, a better safety and tolerance profile has seen the SSRIs become the first choice for treating depression.

But the study's authors are quick to caution that their findings don't mean that citalopram should only be used in women. Raw data from the study show that 24 percent of men achieved remission with the drug, compared with 29 percent of women. The difference in remission rates grew larger once the researchers adjusted for other factors, but the fact remains that many men were helped.

Rather, they note that STAR*D and other studies have shown that many people with depression need to try several treatments to find the one that is right for them and will produce lasting results.

That's why a new study called CO-MED has begun. Young and colleagues from around the country are now enrolling people with depression for this study that will assess the impact of combinations of medications. One of the medications in that study is escitalopram, a cousin of citalopram, but it also includes other common SSRI antidepressants.

Although the current study didn't look at hormonal variations between men and women that might account for the difference in response to citalopram, Young and her colleagues note that animal studies have shown that estrogen modifies the brain systems involved in the activity of serotonin, the key brain chemical affected by SSRI antidepressants.

Another of this study's authors, Susan Kornstein is leading further analysis of the STAR*D results to look for possible differences among women according to their menopausal status and their use of hormone therapy. Meanwhile, Young's research as a member of the U-M Molecular & Behavioral Neuroscience Institute focuses on the interactions of sex hormones and stress response in depression and other mood disorders.

Overall, women are more affected by depression than men, with about 12 percent of women suffering from some form of depression in a given year compared with 6 percent of men. Depression and other mood disorders are the leading cause of disability among women under the age of 45.

The study was funded by the National Institute of Mental Health. Unlike many previous industry-sponsored studies of antidepressants, it included a "real world" sample of people with major depression, and did not exclude people who had a medical illness or history of suicidal thinking. The study did not include people with bipolar disorder. Participants in the study could continue with psychotherapy that they had been undergoing before the start of the study, but could take no other antidepressants.

---

Young EA, Kornstein SG, Marcus SM, et al. Sex differences in response to citalopram: A STAR*D report . J Psychiatr Res. 2008;doi:10.1016/j.jpsychires.2008.07.002   [Abstract]

A study by University of Pennsylvania sociology professor Jason Schnittker found that, while more Americans now believe that mental illness has genetic causes, the nation is no more tolerant of the mentally ill than it was 10 years ago.

The study uses a 2006 replication of the 1996 General Social Survey Mental Health Module to explore trends in public beliefs about mental illness in America, focusing in particular on public support for genetic arguments.

Prior medical-sociology studies reveal that public beliefs about mental illness reflect the dominant mental-illness treatment, the changing nature of media portrayals of the mentally ill and the prevailing wisdom of science and medicine.

Schnittker's study attempts to address why tolerance of the mentally ill hasn't increased along with the rising popularity of a biomedical view of its causes. It finds that different genetic arguments have, in fact, become more popular but have very different associations depending on the mental illness being considered.

"In the case of schizophrenia, genetic arguments are associated with fears regarding violence," Schnittker said. "In fact, attributing schizophrenia to genes is no different from attributing it to bad character - either way Americans see those with schizophrenia as 'damaged' in some essential way and, therefore, likely to be violent. However, when applied to depression, genetic arguments have very different connotations: they are associated with social acceptance. If you imagine that someone's depression is a genetic problem, the condition seems more real and less blameworthy: it's in their genes, they're not weak, so I should accept them for who they are."

The study also shows that genetic arguments are associated with recommending medical treatment but are not associated with the perceived likelihood of improvement.

"While the stigma surrounding mental illness has not diminished, the rate of treatment for psychiatric disorders has increased," Schnittker wrote. "The culture surrounding mental illness has become more treatment-focused with direct-to-consumer advertising of psychiatric medications now a mainstay of popular media."

According to Schnittker's research, genetic arguments have, in fact, increased public support for medical treatment but at the same time aren't clearly associated with improvements in overall tolerance levels. The study explores tolerance in terms of social distancing: unwillingness to live next door to a mentally ill person, have a group home for the mentally ill in the neighborhood, spend an evening socializing with a mentally ill person, work closely with such a person on the job, make friends with someone with a mental illness or have a mentally ill person marry into the family.

---

Schnittker J. An uncertain revolution: Why the rise of a genetic model of mental illness has not increased tolerance. Soc Sci Med. 2008 Aug;doi:10.1016/j.socscimed.2008.07.007   [Abstract]

Mood disorders, including postpartum depression, have long been treated with antidepressants that affect the mood-regulating brain neurotransmitter serotonin. Now researchers have for the first time demonstrated in mice that critical postpartum mothering behaviors and offspring survival also depend on proper functioning of serotonin-secreting neurons.

Mouse mothers genetically bred to have impaired brain serotonin neurons failed to build proper nests and to keep their pups warm in huddles, resulting in their succumbing to exposure. Female mice whose serotonin systems were partially restored early in brain development showed improved mothering behaviors as adults, suggesting that even subtle serotonin enhancements during critical growth periods can likely improve outcomes for future offspring.

"Despite the prevalence of postpartum depression and the frequent use of serotonin selective reuptake inhibitor antidepressants to treat this disorder, our findings are the first to directly demonstrate an important role for the serotonin system in reproductive success" said NIMH grantee Evan Deneris, of Case Western Reserve University. Deneris and colleagues report their findings in the September 2008 Nature Neuroscience.

Deneris and colleagues had previously shown that mice genetically engineered to lack a key gene expression factor called Pet-1 fail to properly develop serotonin neurons and as adults are usually highly aggressive and anxious. However, the mouse mothers in the current study displayed little anxiety, consistent with known effects of being in a lactating state.

Control mouse mothers huddled their offspring in tidy nests for warmth, while mothers deficient in serotonin neurons ignored scattered pups tossing and turning amid disheveled bedding material. Unlike these animals, pups rescued from serotonin-deficient mothers on the first day after birth and nurtured by normal control mothers survived.

Next, the investigators used a genetic cousin of Pet-1 to engineer strains of partially "rescued" mice with serotonin systems functioning at levels in between those of normal control mice and the Pet-1 gene knockout mice. These animals showed an intermediate level of maternal care and their offspring survival rates were in between those of control and the Pet-1 knockout strains.

Since serotonin is probably required during the early postnatal period for the normal maturation of circuitry governing emotional behaviors, the abnormal nurturing shown by Pet-1- deficient mouse mothers could be the result of defective circuitry governing maternal motivation and reward, say the researchers.

---

Lerch-Haner JK, Frierson D, Crawford LK, et al. Serotonergic transcriptional programming determines maternal behavior and offspring survival. Nat Neurosci. 2008 Aug;9(11):1001-03   [Abstract]

We all know the saying: "Sticks and stones may break my bones, but words will never hurt me," but is this proverb actually true?

According to some researchers, words may pack a harder punch that we realize. Psychologists Zhansheng Chen and Kipling D. Williams of Purdue University, Julie Fitness of Macquarie University, and Nicola C. Newton of the University of New South Wales found that the pain of physical events may fade with time, while the pain of social occurrences can be reinstantiated through memory retrievals.

The researchers set up four experiments to demonstrate this finding. In the first two experiments, participants reported the amount of pain they felt while trying to relive a physically or a socially painful experience. After writing detailed accounts of each experience, the participants reported how they felt.

The last two experiments were similar to the first two, except participants were asked to work on some cognitive tasks with different levels of difficulty after reliving a socially or physically painful event.

The results, published in the August issue of Psychological Science are clear. Participants who had to recall a socially painful experience reported stronger feelings of pain and relived the experience more intensely than those who had to recall a physically painful event. Furthermore, participants who only had to recall a physically painful event performed better on the difficult mental tasks in comparison to those who had to relive a socially painful event.

A possible explanation for these results could be the evolution of the human brain, specifically in the cerebral cortex, which is responsible for complex thinking, perception and language processing.

"The evolution of the cerebral cortex certainly improved the ability of human beings to create and adapt; to function in and with groups, communities, and culture; and to respond to pain associated with social interactions," the authors wrote. "However, the cerebral cortex may also have had an unintended effect of allowing humans to relive, re-experience, and suffer from social pain."

---

Chen Z, Williams KD, Fitness J, Newton NC. When Hurt Will Not Heal: Exploring the Capacity to Relive Social and Physical Pain. Psychol. Sci 2008 Aug;19(5):789-795.   [Abstract]

Keith Herrell

A patient who receives a diagnosis of Parkinson's disease might become depressed, and understandably so. But does the depression then exacerbate the progression of Parkinson's?

That's one of the questions a team of University of Cincinnati researchers is studying, with the help of a $1.7 million grant from the National Institutes of Health (NIH).

Parkinson's disease is a degenerative neurological disorder involving the death of dopamine-producing neurons, deep within the brain. Depression is highly prevalent in Parkinson's disease, previous research has found.

Principal investigator Kim Seroogy, PhD, and co-investigator James Herman, PhD, are studying a stress-induced model of depression and Parkinson's in rodents. Seroogy is a professor of neurology and director of the Selma Schottenstein Harris Lab for Research in Parkinson's at the James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders. Herman is a professor of psychiatry and director of the university's neuroscience graduate program.

Parkinson's-induced rodents are stressed in a variety of ways, such as being placed briefly in a cold room or a crowded setting. In studying the results, the UC team hopes to gain insight into a problem Seroogy likens to the classic chicken-and-egg question: Which comes first, Parkinson's or depression?

"There are two schools of thought on co-morbidity of depression and Parkinson's," says Seroogy. "One is that the onset of depression precedes and possibly leads to Parkinson's. The other is that Parkinson's disease predisposes for depression. Clinically, there's evidence for both of those lines of thinking."

The NIH grant will enable the UC team to examine the question and, as Seroogy puts it, "have it surrounded."

"We're going to have some groups that undergo depression first, then the Parkinson's, and then we'll do the reverse," he says. "Then there will be some that are combined-depression, then parkinsonism, then further depression."

In pilot models so far, Seroogy and Herman have found that in those animals that have stress combined with Parkinson's, their normal loss of dopamine cells in the brain is accelerated. In addition, the movements of their impaired limbs also worsened in the behaviors that were tested.

"So stress-induced depression exacerbates problems with movement, and also causes the relevant brain cells to die faster," Seroogy says.

Learning more about the relationship between depression and Parkinson's will provide insight into possible treatments of Parkinson's, Seroogy says.

"You might ask, 'Why don't we just prescribe antidepressants?'" he adds. "Well, we do. But there are no really definitive epidemiological studies or long-term assessments of the effects of antidepressants on the progression of Parkinson's."

Seroogy and Herman will explore that, plus the possibility that antidepressants can protect the brain from Parkinson's disease.

"Not only could they reduce depression, but they might actually protect dopamine cells in the brain and thus slow the progression of Parkinson's," says Seroogy.

Seroogy and Herman began their research into depression and Parkinson's with a $14,000 grant from the Sunflower Revolution Encore, a private fund-raiser hosted by Melody Sawyer Richardson in 2005. Two years later, they received a $50,000 grant from the Davis Phinney Foundation to continue their research, which was also supported in the interim by about $20,000 from the Parkinson's Disease Support Network of Ohio, Kentucky and Indiana.

"We're gratified that an investment in our research by the local community and the Davis Phinney Foundation has now led to a five-year NIH grant that will allow us to investigate how stress causes enhanced parkinsonian symptoms, and how to prevent stress from causing further damage to the parkinsonian brain," says Seroogy.

Most people would agree that stress increases your risk for illness and this is particularly true for severe long-term stresses, such as caring for a family member with a chronic medical illness. However, we still have a relatively limited understanding of exactly how stress contributes to the risk for illness. In the August issue of Biological Psychiatry, researchers shed new light on one link between stress and illness by describing a mechanism through which stress alters immune function.

In a preliminary study, Gregory E. Miller Ph.D. and colleagues found that the pattern of gene expression differed between caregivers of family members with cancer relative to a matched group of individuals who did not have this type of life stress.

They found that among the caregivers, even though they had normal cortisol levels in their blood, the pattern of gene expression in the monocytes, a type of white blood cell involved in the body's immune response, was altered so that they were relatively less responsive to the anti-inflammatory actions of cortisol, but relatively more responsive to pro-inflammatory actions of a transcription factor called nuclear factor-kappa B, or NF-κB.

Miller explains that, although "caregivers have similar cortisol levels as controls, their cells seem to be 'hearing' less of this signal. In other words, something goes awry in caregivers' white blood cells so they are not able to 'receive' the signal from cortisol that tells them to shut down inflammation."

Thus, the current findings might help to explain why the caregivers would seem to be in a chronic pro-inflammatory state, a condition of immunologic activation. This activated state could contribute to the risk for a number of medical illnesses, such as depression, heart disease, and diabetes. Dr Miller remarks that part of the importance of these findings is "because people have traditionally thought that higher cortisol is the reason that stress contributes to disease, but this work shows that, at least in caregivers, it's actually the opposite - there's too little cortisol signal being heard by the cells, rather than too much."

However, many important related questions still remain unanswered, as noted by John H. Krystal, MD, Editor of Biological Psychiatry. He comments that in addition to not knowing how stress produces these altered patterns of gene expression in the immune system, "we don't know how to account for the resilience of some stressed people exposed to severe sustained stress or the vulnerability of some people to relatively mild stress." He adds that "The better that we understand the underlying molecular mechanisms that link stress to illness, the more likely we are to make progress in answering these important questions."

---

Miller GE, Chen E, Sze J, et al. A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling. Biol Psychiatry. 2008 Aug 15;64(4):266-72   [