Aaron Levin

Another report from TADS finds that continuing depression treatment - regardless of modality - helps more adolescent patients.

Most patients who achieved a sustained response to treatment in the first 12 weeks of the Treatment for Adolescents With Depression Study (TADS) maintained their gains at 36 weeks, while over half of those who did not achieve a sustained response at 12 weeks did so with further treatment, according to the investigators' latest report.

David D, Szentagotai A, Lupu V, Cosman D.

Babes-Bolyai University, Romania; Iuliu Hatieganu University of Medicine and Pharmacy, Romania

A randomized clinical trial was undertaken to investigate the relative efficacy of rational-emotive behavior therapy (REBT), cognitive therapy (CT), and pharmacotherapy in the treatment of 170 outpatients with nonpsychotic major depressive disorder.

The patients were randomly assigned to one of the following: 14 weeks of REBT, 14 weeks of CT, or 14 weeks of pharmacotherapy (fluoxetine). The outcome measures used were the Hamilton Rating Scale for Depression and the Beck Depression Inventory.

No differences among treatment conditions at posttest were observed. A larger effect of REBT (significant) and CT (nonsignificant) over pharmacotherapy at 6 months follow-up was noted on the Hamilton Rating Scale for Depression only.

(Text has been reformatted for clarity; ed.)

Rottach KG, Schaner BM, Kirch MH, Zivotofsky AZ, Teufel LM, Gallwitz T, Messer T.

Hafenmarkt 12, 87600 Kaufbeuren, Germany.

Although of clinical interest, the question is still not fully answered whether antidepressants (AD) can cause or exacerbate restless legs syndrome (RLS). The literature provides contradictory information. This study addresses this problem for the class of second generation AD.

In four neurological offices, all patients treated for the first time with an AD were prospectively observed with regard to the question of whether RLS occurred or pre-existing RLS worsened as a result of the medication. Because initial treatment in the participating offices is mainly executed with "modern" selective AD, the study was restricted to these drugs (fluoxetine, paroxetine, citalopram, sertraline, escitalopram, venlafaxine, duloxetine, reboxetine, and mirtazapine).

In 9% of patients, RLS was recorded as a side effect related to the administration of AD. The frequency of this side effect varied among the drugs. The problem is most pronounced with mirtazapine provoking or deteriorating RLS in 28% of patients. By contrast, no case occurred during use of reboxetine. As for the other AD, the rate of newly occurred and deteriorated RLS, ranged from 5% to 10%. Typically, RLS occurred during the initial days of treatment.

Although children as young as 5 can be diagnosed with obsessive-compulsive disorder (OCD), few research studies have looked at treatments specifically geared toward young children with this disorder. Now, a new study from the Bradley Hasbro Children's Research Center provides some of the first evidence-based data on a successful intervention for early childhood OCD.

According to the study's findings, published the Journal of the American Academy of Child and Adolescent Psychiatry, children with OCD between the ages of 5 and 8 may benefit from a form of psychotherapy, known as family-based cognitive behavioral therapy (CBT), that is uniquely tailored to the child's developmental needs and family context. The overall focus of family-based CBT is to provide both child and parents with a set of tools to help them understand, manage and reduce OCD symptoms.

"If left untreated, early childhood OCD can severely disrupt and impair a child's development and functioning and can extend into adulthood. Despite this risk, clinicians do not have a proven treatment model for these young children," says lead author Jennifer B. Freeman, PhD, of the Bradley Hasbro Children's Research Center and an assistant professor of psychiatry/human behavior (research) at The Warren Alpert Medical School of Brown University.

"Based on our findings, we believe that family-based cognitive behavioral therapy for early childhood OCD offers a promising intervention that may help to minimize the chronic nature of OCD and decrease the morbidity of this debilitating illness," she adds.

Researchers worked with 42 young children with OCD who were randomized to receive 12 sessions - completed over 14 weeks - of either family-based CBT or family-based relaxation treatment (RT), an approach that teaches the family and child relaxation techniques aimed at reducing some of the stress inherent with OCD. Just over half of the patients were randomly assigned to CBT and 48 percent were assigned to RT. Overall, 74 percent of patients completed all 14 weeks of treatment.

The CBT program was found to be significantly more effective than RT in decreasing OCD symptoms and, most importantly, helping a large number of children achieve clinical remission. Specifically, 69 percent of the children who completed all 14 weeks of CBT treatment achieved remission compared to 20 percent who fully completed the RT program. Even those children who started, but did not complete, the CBT program did well, with 50 percent achieving clinical remission.

"An important takeaway from this study is that children in this age range can actively participate in and benefit from CBT that is appropriately tailored to their cognitive developmental level," Freeman says. "And from a research perspective, these findings are particularly promising because they demonstrate that it's possible to recruit, treat and collect data about young children with OCD."

The family-based CBT method modeled in the study draws on successful approaches used with older children but also contains innovative elements that have been specifically tailored to children ages 5 to 8, with special attention paid to the child's cognitive and developmental level and awareness of a child's involvement in and dependence on a family system.

Freeman points out that there are a number of reasons why younger children experiencing OCD require this kind of tailored approach. "Developmentally, younger children generally have less sophisticated emotion awareness and expression skills than older children. Also, younger children rely on parents for guidance and direction more so than older children and parents may be more likely to inadvertently reinforce or even actively accommodate a young child's rituals," she says.

Based on the study's findings, Freeman and colleagues offer the following recommendations:

• Treatment of children experiencing early childhood-onset OCD will be most effective if parents are involved in all phases of treatment.



• Clinicians should consider the child's unique developmental characteristics and tailor psychoeducation, exposures and homework accordingly.



• Clinicians should take time to understand the family context and, in particular, the parents' response to their child's anxieties.



• Teach parents to tolerate their own anxiety about their child's level of distress.



• Use humor generously.

According to the American Academy of Child and Adolescent Psychiatry, as many as 1 in 200 children and adolescents struggle with OCD, an anxiety disorder characterized by recurrent, intense obsessions and/or compulsions that cause severe discomfort and interfere with daily functioning. Compulsions are repetitive behaviors such as hand washing, counting, checking, or cleaning and they are often performed with the hope of preventing obsessive thoughts or making them go away. Performing these so-called "rituals," however, provides only temporary relief, and not performing them can cause significant anxiety or distress and can interfere with a child's normal routine, academic functioning, social activities, or relationships.

The study was funded by a grant from the National Institute of Mental Health.

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Freeman JB, Garcia AM, Coyne L, et al. Early Childhood OCD: Preliminary Findings From a Family-Based Cognitive-Behavioral Approach. J Am Acad Child Adolesc Psychiatry. 2008 May;47(5):593-602.   [Abstract]

By Tina Hesman Saey

Genes' chemical clothes may underlie the biology behind mental illness

In research circles the debate is settled. Psychiatric illnesses are disorders rooted in biology.

As convincing as the evidence is, mysteries still fog our understanding of mental illnesses. Yes, the disorders stem from problems in the brain, but "on the other hand, for time and ages people have been looking at brains under the microscope, and they don't see much," says Schahram Akbarian, a psychiatrist and neuroscientist at the University of Massachusetts Medical School in Worcester. No lesions, malformations, scars or other outward signs distinguish a mentally ill brain from a healthy one.

Carolyn Sachs

KOLOA, HAWAII - Genetic factors might play a role in determining who gets posttraumatic stress disorder after trauma and who gets depression, according to two studies.

In addition, increasing evidence suggests that child abuse and neglect are associated with an increased risk for mood disorders and anxiety disorders such as PTSD, Dr Charles B. Nemeroff said at the annual meeting of the American College of Psychiatrists.

Opatrny L, Delaney JA, Suissa S.

Division of Clinical Epidemiology, and Division of Internal Medicine, McGill University Health Center; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The known biological effects of selective serotonin reuptake inhibitors (SSRI) on platelets are consistent with an increased risk of gastrointestinal haemorrhage in patients on SSRI therapy.

Previous research supports this increased risk among SSRI users with a large increase in bleeding risk observed.

WHAT THIS STUDY ADDS: This large study was able to compare the effects of different classes of antidepressant as well as to test for drug-drug interactions with warfarin.

The discovery of alcohol abuse as a strong confounder may partially explain the very high risks of bleed seen in previous studies that did not adjust for this confounder.

AIMS: (i) To determine the effects of selective serotonin reuptake inhibitors (SSRI) and other classes of antidepressants on upper gastro-intestinal (GI) haemorrhage and (ii) to assess the drug-drug interaction effects of antidepressants and warfarin or clopidogrel on the risk of GI haemorrhage.

METHODS: This was a population-based case control study in the General Practice Research Database (GPRD). Cases with a first episode of upper GI haemorrhage between 2000 and 2005 were matched with up to 10 controls. Exposure to the study drugs was defined by a prescription issued in the 90 days before the index date. Rate ratios were estimated using conditional logistic regression.

RESULTS: Four thousand and twenty-eight cases of GI haemorrhage and 40,171 controls were identified. The excess risk of GI haemorrhage with SSRI use was small (Rate Ratio [RR]: 1.3; 95% confidence interval [CI]: 1.1, 1.6) and null with exposure to tricyclic antidepressants (TCAs) (RR 1.0; 95% CI: 0.8, 1.3). The risk of GI haemorrhage was highest with venlafaxine use (RR: 1.9; 95% CI: 1.3, 2.6). There was no drug-drug interaction between warfarin anticoagulation and antidepressant use.

CONCLUSIONS: This study supports a small increased risk of upper GI haemorrhage with the use of SSRI antidepressants compared with the older TCA drugs, but to a lesser extent than previously reported due to confounding by alcohol use. The small elevation in risk of GI haemorrhage with SSRI and venlafaxine should be weighed against the therapeutic benefit of their use.

(Text has been reformatted for clarity; ed.)

Infants and toddlers whose mothers are severely depressed are almost three times more likely to suffer accidental injuries than other children in the same age group, according to a new study. The study's findings, published today in the Advanced Access edition of the Journal of Pediatric Psychology, suggest that proper treatment for depression would improve not only the mothers' health, but the health of young children as well.

Prior studies have shown that mothers who reported symptoms consistent with clinical depression had children who experienced a significant number of accidental injuries between the ages 3 months to 2 years.

In his study, UAB psychologist David Schwebel, PhD, director of the UAB Youth Safety Lab, examined the difference between mothers with severe, chronic depression and those who were moderately depressed as their children grew from birth to first grade.

A likely cause for the link between severe maternal depression and young children's injury risk is that chronically depressed mothers may not appropriately safeguard the physical environments that children engage in, Schwebel said. Another cause may be that symptoms of depression include inattention, poor concentration and irritability, which "might lead to poor or inconsistent supervision and enforcement of safety-related rules," he said.

Schwebel used a sample of 1,364 mothers included in the National Institute of Child Health and Human Development Study of Early Child Care. The mothers were periodically asked to list all their children's injuries that had required professional medical treatment. Also, on four occasions during the study, the mothers were asked to rate how often they experienced symptoms of depression.

Only 2.5 percent of the mothers in the sample reported severe, clinical depression and 15.5 percent reported being moderately depressed. The researchers found that young children, from birth to 3 years, whose mothers suffered severe, chronic depression, were three times more likely to experience accidental injuries than infants and toddlers whose mothers were only moderately depressed.

The link between severe, chronic depression in mothers and injuries in young children remained consistent even when taking into account the families' socio-economic status, parenting styles, and the children's sex, temperament and behavior.

However, when children grew older, from age 3 to first grade, there was little difference in the injury rates of those whose mothers suffered from severe depression and those who reported being moderately depressed when the children were toddlers.

Although the study did not address why the older children fared better, Schwebel said older children often begin making their own decisions about whether to act in safe or dangerous ways. "Therefore, parents matter a little less - and in particular, inadequate supervision by a depressed mother might not influence the child's safety as much as it does during the toddler years."

Future research should consider the environment in which children are injured and the ages at which children are most susceptible to accidental injuries when supervised by mothers who have depression. The various symptoms of maternal depression such as anger and irritability also should be considered, Schwebel said.

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Schwebel DC, Brezausek CM. Chronic Maternal Depression and Children's Injury Risk. J Pediatr Psychol. 2008 May 12; doi:10.1093/jpepsy/jsn046   [Abstract]

Women and men tend to have different types of stress-related psychological disorders. Women have greater rates of depression and some types of anxiety disorders than men, while men have greater rates of alcohol-use disorders than women. A new study of emotional and alcohol-craving responses to stress has found that when men become upset, they are more likely than women to want alcohol.

"We know that women and men respond to stress differently," said Tara M. Chaplin, associate research scientist at Yale University School of Medicine and first author of the study. "For example, following a stressful experience, women are more likely than men to say that they feel sad or anxious, which may lead to risk for depression and anxiety disorders. Some studies have found that men are more likely to drink alcohol following stress than women. If this becomes a pattern, it could lead to alcohol-use disorders."

As part of a larger study, the researchers exposed 54 healthy adult social drinkers (27 women, 27 men) to three types of imagery scripts - stressful, alcohol-related, and neutral/relaxing - in separate sessions, on separate days and in random order. Chaplin and her colleagues then assessed participants' subjective emotions, behavioral/bodily responses, cardiovascular arousal as indicated by heart rate and blood pressure, and self-reported alcohol craving.

"After listening to the stressful story, women reported more sadness and anxiety than men," said Chaplin, "as well as greater behavioral arousal. But, for the men ... emotional arousal was linked to increases in alcohol craving. In other words, when men are upset, they are more likely to want alcohol."

These findings - in addition to the fact that the men drank more than the women on average - meant that the men had more experience with alcohol, perhaps leading them to turn to alcohol as a way of coping with distress, added Chaplin. "Men's tendency to crave alcohol when upset may be a learned behavior or may be related to known gender differences in reward pathways in the brain," she said. "And this tendency may contribute to risk for alcohol-use disorders."

There is a greater societal acceptance of "emotionality," particularly sadness and anxiety, in women than in men, noted Chaplin.

"Women are more likely than men to focus on negative emotional aspects of stressful circumstances, for example, they tend to 'ruminate' or think over and over again about their negative emotional state," she said. "Men, in contrast, are more likely to distract themselves from negative emotions, to try not to think about these emotions. Our finding that men had greater blood pressure response to stress, but did not report greater sadness and anxiety, may reflect that they are more likely to try to distract themselves from their physiological arousal, possibly through the use of alcohol."

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Chaplin TM, Hong K, Bergquist K, Sinha R. Gender Differences in Response to Emotional Stress: An Assessment Across Subjective, Behavioral, and Physiological Domains and Relations to Alcohol Craving. Alcohol Clin Exp Res. 2008;doi: 10.1111/j.1530-0277.2008.00679.x   [Abstract]

While 30 to 50 percent of people with Gilles de la Tourette Syndrome are also affected with obsessive compulsive disorder (OCD), both illnesses might have a distinct neurocognitive profile, according to a new study published in the journal Progress in Neuro-Psychopharmacology & Brain Psychiatry by researchers from the Université de Montréal and the Fernand-Seguin Research Centre of the Louis-H Lafontaine Hospital.

"In the study of cerebral activity or the relationship with working memory and attention, this was the first study to show a clear dissociation between OCD and Tourette's dimensions. This could have a major impact in the treatment. It is difficult to treat Tourette's symptoms if you don't identify and address symptoms of OCD first," said Université de Montréal associate researcher Dr Marc Lavoie, who completed the study with students Geneviève Thibault and Mihaela Felezeu, and clinician collaborators Kieron O'Connor, Christo Todorov and Emmanuel Stip.

Gilles de la Tourette Syndrome is a complex neuropsychiatric disorder, marked by increasing motor and phonic tics, which begins in childhood and peaked at 11 years old. The illness affects 0.05 to 3 percent of children and about 1 percent of adults. OCD, an anxiety disorder characterized by obsessions and compulsions, affects 2.5 percent of the population.

"When testing patients, we found that brain regions associated with working memory among people affected by Tourette's are much more active than control subjects when stimulated, while regions associated with working memory in OCD patients decreased," explained Dr Lavoie.

"This study will help clinicians provide better diagnostic and treatment by isolating therapies that will better help OCD or Tourette's patients," said Dr Lavoie.

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Thibault G, Felezeu M, O'Connor KP, et al. Influence of comorbid obsessive-compulsive symptoms on brain event-related potentials in Gilles de la Tourette syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr;32(3):803-815   [Abstract]

Girls are twice as likely as adolescent boys to suffer a major depressive episode

About 2.1 million teens aged 12 to 17 experienced a major depressive episode in the past year, according to a new nationwide report by the Substance Abuse and Mental Health Services Administration. For almost half of the teens, depression drastically reduced their abilities to deal with aspects of their daily lives, the report said.

Overall, 8.5 percent of adolescents, the equivalent of one in every 12, experienced a major depressive episode, but there were striking differences by gender, with 12.7 percent of females and 4.6 percent of males reporting the conditions.

"Fortunately, depression responds very well to early intervention and treatment," said SAMHSA Administrator Terry Cline, Ph.D. "Parents concerned about their child's mental health should seek help with the same urgency as with any other medical condition. Appropriate mental health care can help their child recover and thrive."

The report defines a major depressive episode as a period of two weeks or longer of depressed mood or loss of interest or pleasure, and at least four other symptoms reflecting a change in functioning (for example, problems with sleep, energy, concentration and self-image). This is the definition established by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association.

Major Depressive Episode among Youths Aged 12 to 17 in the United States of America: 2006 also reveals the often devastating effect these major depressive episodes can have on adolescents. Nearly half of adolescents experiencing major depression (48.3%) report that it severely impaired their ability to function in at least one of four major areas of their everyday lives (home life, school/work, family relationships, and social life). Adolescents reporting the most severe impairment reported that they were unable to carry out normal activities on an average of 58.4 days in the past year.

The report is based on combined data from the 2004 to 2006 National Surveys on Drug Use and Health (NSDUH) involving responses from 67,706 people aged 12 to 17 throughout the United States. The survey is based on a scientific random sample of households throughout the United States, and professional field representatives personally visit each household to conduct the survey.

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Substance Abuse and Mental Health Services Administration, Office of Applied Studies. (May 13, 2008). The NSDUH Report: Major Depressive Episode among Youths Aged 12 to 17 in the United States: 2004 to 2006. Rockville, MD.  [HTML | PDF ()]

Antidepressants may help body fight HIV and cancer" was the headline in The Independent today. The newspaper article was on research that suggests that antidepressant drugs may help the immune system to fight off serious infection. The newspaper says the drugs could increase the activity of Natural Killer (NK) cells, a part of the immune system that targets cancerous and infected cells and induces "apoptosis" or "cell suicide". The Daily Mirror focuses on the possible effect on cancerous cells, with a headline claiming "Big C hope for Prozac".

Although the current research will be of scientific and medical interest, claims about the efficacy of antidepressants in HIV and cancer should not be made prematurely. This study involved laboratory research on blood samples from a specific group of women with HIV, and its findings cannot be generalized outside of this context. Much further research will be needed in people with HIV to see whether antidepressants could have any role in enhancing immunity.

At the current time, antidepressants should continue to be viewed in their role as treatments of depression, stress and anxiety - not as potential treatments for HIV or anti-cancer drugs.

The use of beta blocker drugs before surgery to cut the risk of heart problems may be counter-productive, a study suggests.

..."Also, the results of this trial - of a relatively high dose of a beta blocker given before surgery - do not mean patients stabilised on long term beta blocker therapy will be at increased risk if they have surgery."

(Emphasis added, Ed.)

The post-university years can start out tough. The good news: it gets better.

A new University of Alberta study of almost 600 of its graduates (ages 20-29 years old) tracked mental health symptoms in participants for seven years post-graduation and looked at how key events like leaving home and becoming a parent were related to depression and anger. Graduates showed a significant decrease in depressive symptoms over the seven years. Expressed anger also declined over time after graduation, suggesting improved mental health.

The researchers also found that while home may be a haven for young people in the early years of adulthood, the longer they stay at home, or if they return home, the more likely they are to experience symptoms of depression. Previous research has found that more than half of students under 25 in four-year university programs lived with their parents.

In this study, it was shown that younger participants were more depressed at times when they lived on their own, while older participants were more depressed while they lived with their parents.

"Some key events, such as leaving home, may throw emerging adults a little off kilter, depending on the timing of the transition," said Nancy Galambos, University of Alberta psychology professor. "Leaving home too soon can be challenging in ways that have the potential to affect mental health."

It was revealed that women were more depressed and angry at the start of the study than men. Also, anger increased when participants became parents.

"Although we generally welcome parenthood as a positive experience, we found that people who became parents became angrier, and this was especially pronounced for mothers," said Harvey Krahn, University of Alberta chair of sociology. "The transition to parenthood produces a new set of demands on the couple that may be difficult to cope with as parents have to negotiate a whole new set of family responsibilities."

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Galambos NL, Krahn HJ. Depression and Anger Trajectories During the Transition to Adulthood. J Marriage Fam. 2008;70(1):15-27   [Full text]

Researchers find link between altered dopamine activity and social anxiety disorder

Using single-photon emission computed tomography (SPECT), researchers in The Netherlands were able to detect biochemical differences in the brains of individuals with social anxiety disorder (also known as social phobia), providing evidence of a long-suspected biological cause for the dysfunction.

The study compared densities of elements of the serotonin and dopamine neurotransmitter systems in the brains of 12 people diagnosed with social anxiety disorder, but who had not taken medication to treat it, and a control group of 12 healthy people who were matched by sex and age.

Both groups were injected with a radioactive compound that binds with elements of the brain's serotonin and dopamine systems. Once administered, the radiotracer revealed functional alterations in these systems by measuring the radioactive binding in the thalamus, midbrain and pons (known to be acted upon by serotonin) and in the striatum (known to be acted upon by dopamine). The altered uptake activity in these regions indicated a greater level of disordered function.

"Our study provides direct evidence for the involvement of the brain's dopaminergic system in social anxiety disorder in patients who had no prior exposure to medication," said Dr van der Wee, M.D., Ph.D., at the department of psychiatry and the Leiden Institute for Brain and Cognition at the Leiden University Medical Center, Leiden. "It demonstrates that social anxiety has a physical, brain dependent component."

Serotonin and dopamine neurotransmitters act upon receptors in the brain. If these neurotransmitter systems are out of balance, messages do not propagate through the brain properly. This can alter the way the brain reacts to normal social situations, leading to anxiety.

Other neuroimaging studies have shown abnormalities in glucose and oxygen consumption in the brain, according to van der Wee, who also points to causality as an additional issue. "Most of the people involved in these earlier studies were known to be already suffering from the disorder, so we do not know if the abnormalities were present before the onset of the disorder," he said.

Based on earlier studies, some researchers have suggested that social anxiety disorder is a result of the interplay between a genetic or acquired biological vulnerability and environment. More recent research has indicated that social anxiety disorder might be related to an imbalance of the serotonin system. This is the first time the brain's dopaminergic system was examined directly.

"Although there are no direct implications for treatment as a result of this study yet, it is another piece of evidence showing biological abnormalities, which may lead to new therapeutic approaches and insight into the origins of the disorder," said Dr van der Wee.

According to the National Institute of Mental Health, social anxiety disorder affects approximately 15 million American adults and is the third most common mental disorder in the United States, after depression and alcohol dependence. The essential feature of the disorder is the fear of being evaluated by others, with the expectation that such an assessment will be negative and embarrassing. It tends to run a chronic and unremitting course and often leads to the development of alcoholism and depression. The disorder most often surfaces in adolescence or early adulthood, but it can occur at any time, including childhood.

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van der Wee NJ, van Veen JF, Stevens H, et al. Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication-Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-ß-(4-Iodophenyl)-Tropane SPECT. J Nucl Med 2008 49: 757-763.   [Abstract]

by Nicole Kasielke

Emotional memories of traumatic life events such as accidents, war experiences or serious illnesses are stored in a particularly robust way by the brain. This renders effective treatment very difficult. Researchers at ETH Zurich and the University of Zurich have now successfully tracked down the molecular bases of these strong, very persistent memories.

It is known that emotional memories of both a positive and a negative kind are stored by our brain in a particularly robust way. Consequently they have a very large effect on our behavior and, in the case of adverse memories, they can place considerable restrictions on the way we go about our lives. As a result, we may avoid places, smells or objects that remind us of the traumatic experience, because they may trigger severe anxieties.

Isabelle Mansuy, Professor of Cellular Neurobiology at ETH Zurich and of Molecular and Cognitive Neurosciences at the University of Zurich, and her research group have now shown that the enzyme calcineurin and the gene regulation factor Zif268 (also known as Egr1 - Early Growth Response Protein 1) decisively determine the intensity of emotional memories. For the first time, this has enabled the regulatory processes at the synapse, which are important for emotional memories, to be linked to the processes in the cell nucleus.

The generation of very persistent memories in the shortest possible time needs molecules in the brain that are not only activated rapidly but which also efficiently control the signalling pathways of long-term information storage in the brain. This is why the protein phosphatase calcineurin, which was already known to have a negative regulatory effect on learning and memory, was a very promising candidate for the Swiss researchers.

Mice were used as the model system because their learning processes are very similar to that of humans, and established behavioral tests already exist.

The researchers conditioned the mice to associate a sugar solution with nausea. This association persists for many months causing the mice to avoid the sugar solution during this period. However, their aversion can be overcome slowly through intensive training.

Mansuy explains that "Emotional memories are not simply erased. Oppressive negative memories need to be actively replaced by positive memories." She says it is important at the same time to understand that the negative memories do not disappear, they merely slide down in a kind of priority list and are outweighed by the more recently learned positive memories. Mansuy says "This process is not final and absolute, since the priority list can change again."

Karsten Baumgärtel, a post-doctoral researcher in Mansuy's group, stresses that there is a big difference between emotional memories and learned knowledge. "It is entirely possible for facts to vanish completely from the memory, whereas in extreme cases emotional recollections remain stored for a whole lifetime. Active intervention is necessary to reduce the priority level of negative memories."

Studies of the amygdala, a part of the brain important for emotional perception, showed reduced activity of the enzyme calcineurin in conditioned mice compared to mice in which no association with nausea had been generated. Because calcineurin is a negative regulator of learning and memory, its activity needs to be reduced to enable strong memorization.

To gain more evidence for the role of calcineurin in the memory process, the researchers used transgenic mice in which they were able to selectively activate or deactivate the enzyme in brain nerve cells. Mansuy explains that "This selective activation and inactivation in nerve cells is important because calcineurin is an enzyme that occurs in many cells. For example it also plays an important part in the immune defence system."

As the researchers expected, inactivating calcineurin strengthened the memory of the association between sugar solution and nausea, whereas the memory was weakened by increased calcineurin activity. The researchers were also able to demonstrate that the time needed to suppress the negative memory by a purely positive memory could be prolonged or shortened respectively by this intervention.

Inactivating calcineurin also causes increased expression of the gene regulator Zif268 in the amygdala. Zif268 is responsible for regulating a wide variety of important genes that play a role in the signal processing of memories and learning. Simulating this increased expression of Zif268 in transgenic mice intensified memory in a similar way to the inactivation of calcineurin.

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Baumgärtel K, Genoux D, Welzl H, et al. Control of the establishment of aversive memory by calcineurin and Zif268. Nat Neurosci. 2008 May;11:572-578   [Abstract]

Uriel Halbreich, MD

Complementary and alternative medicine (CAM) is very popular in the United States, Canada and other Western societies, and the number of patients seeking treatment by CAM practitioners is increasing. This trend also affects treatment-seeking patients with affective disorders. Many patients and mental health providers update their information and formulate opinions and decisions based on second-hand digested summaries and scientific reviews of the literature. This results in the proliferation of review articles and journals that are exclusively dedicated to reviews. Since most medical schools do not teach CAM and most continuing medical education programs still ignore these subjects, it is of interest to examine the reliability of reviews that claim to be "systematic" and not to take their procedures and conclusions for granted.

by Kara Gavin

Depressed people may have far fewer of the receptors for some of the brain's "feel good" stress-response chemicals than non-depressed people, new University of Michigan Depression Center research shows.

And even among depressed people, the numbers of these receptors can vary greatly. What's more, the number of receptors a depressed person has appears to be linked with the severity of their symptoms - and the chances that they'll feel better after taking a medication.

These preliminary findings, presented at the American Psychiatric Association's annual meeting in Washington, D.C., amplify a growing understanding of depression as a condition that affects different people in different ways. The new data, and other researchers' findings, are showing that depression is solidly rooted in genetic and molecular factors that are unique to each individual.

The lead University of Michigan researcher, Jon-Kar Zubieta, MD, PhD, says these new results bolster what other researchers have been finding in recent years.

"There's a substantial amount of biological difference even among people who have major depression, which is just as important as the biological differences between people with depression and people without," he says. "The more we can understand about these differences, the better we can address treatment to the individual and have the greatest effect on symptoms."

At the APA meeting, Zubieta presented data from positron emission tomography, or PET, scans of the brains of patients who met the criteria for major depression but had not yet received treatment for it. Those scans were compared with scans of the brains of non-depressed comparison volunteers.

In one group of depressed and non-depressed volunteers, the scans were made using a tracer that can reveal the location and concentration of a particular type of receptor. Called the 5HT_1a receptor, it allows brain cells to receive signals from serotonin, a chemical neurotransmitter produced by the brain.

Serotonin levels in the brain are linked to depression, but the importance of 5HT_1a receptor concentrations in the brains of depressed people has been cloudy. This is why Zubieta's team chose to scan only people who had not yet received antidepressant medications, since some such medications may actually encourage the brain's cells to make more serotonin receptors - and mask the actual level of receptors that the person has naturally.

In the study, 5HT_1a receptor concentrations were markedly lower in depressed people compared with non-depressed people, in both the left and right hippocampus regions of the brain.

But even among depressed people, the lower a person's 5HT_1a receptor levels were, the worse he or she scored on assessments of the ability to function day to day - and the less likely he or she was to get relief from symptoms when the researchers prescribed a common antidepressant.

This finding of individual variation may help explain why in current depression treatment, some patients find great relief from a medication that doesn't help other equally depressed patients, says Zubieta.

The other group of volunteers - both depressed and non-depressed - received PET scans with a tracer that allowed the researchers to see the mu-opioid receptors in their brains. These receptors are the gateway for signals sent by chemicals called endogenous opioids - the brain's natural "painkillers" - which are involved in stress response, including response to pain.

The endogenous opioids, or endorphins, have become known as a "feel good" chemicals involved in reinforcing rewarding experiences. Illicit drugs such as heroin also act upon mu-opioid receptors, creating the "high" sensation and probably playing a role in the addiction process.

In this group of depressed and non-depressed volunteers, the researchers studied the distribution of the mu-opioid receptors and looked at how active the receptors were when the volunteers were asked to summon a sad memory or scenario to mind.

Depressed volunteers had lower concentrations of mu-opioid receptors to begin with. But when they underwent the "sadness challenge," those receptors were much more active than the receptors in non-depressed people. And, just as with the serotonin 5HT_1a receptors, the fewer mu-opioid receptors a person had, the less well he or she responded to an antidepressant medication.

The study was funded by the National Institutes of Health, by the Pritzker Foundation and by NARSAD, a leading mental health charity.

Dr Zubieta and his colleagues are now working to submit these new data for publication. At the same time, they are continuing to recruit depressed volunteers who are not taking medication for more brain-imaging studies. To find out more about how to participate in depression research at the University of Michigan Depression Center, visit www.umengage.org.

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Zubieta JK. Dysregulation of Stress-Regulated Neuro- transmitter Systems in Major Depression. Symposium presentation 35-D, APA Annual meeting Washington DC, 2008 May 6.

MedWire News: Synaptic plasticity appears to be involved in the development of mood disorders during childhood and adolescence, with the neurotrophic tyrosine kinase receptor 3 (NTRK3) gene playing a specific role, says an international team of scientists.

As number of drug warnings rise, investigators search for reasons why

By Fran Kritz
Special to msnbc.com

When Kate Miller of Queensbury, N.Y., filled a new allergy drug prescription for her 15-year-old son, Cody, last July, she hoped it would improve his bothersome allergy symptoms. Now, Miller is wondering whether a possible side effect of the drug, Singulair, caused Cody - who she describes as a happy, athletic teenager - to take his own life about a month later.

Miller isn't alone. Physicians or patients have filed anecdotal reports with drug companies or the Food and Drug Administration on at least six drugs or drug classes that may have been linked to episodes of suicidal thoughts or actions. In just the past few months, the FDA has released several advisory notices to both doctors and the public about drugs linked to suicidal thoughts or actions, including Singulair, epilepsy drugs and the smoking-cessation drug Chantix. Reports have also been filed on antidepressants, the influenza drug Tamiflu and the acne medicine Accutane.

Altamura AC, Dell'Osso B, D'Urso N, Russo M, Fumagalli S, Mundo E.

Department of Psychiatry, University of Milan, Italy;

Introduction: The aim of the present study was to investigate the impact of the duration of untreated illness (DUI)-defined as the time elapsing between the onset of generalized anxiety disorder (GAD) and the first adequate pharmacologic treatment-on treatment response and clinical course in a sample of subjects with GAD.

Methods: One hundred patients with GAD, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria, were enrolled and their main demographic and clinical features collected. Patients were then treated with selective serotonin reuptake inhibitors or venlafaxine for 8 weeks in open-label conditions. Treatment response and other clinical variables were analyzed after dividing the sample into two groups according to DUI (DUI lt;12 months and DUI >12 months).

Results: When the DUI was computed with respect to the first antidepressant treatment (DUI-AD), a higher improvement (Clinical Global Impressions-Severity of Illness scale) after the pharmacologic treatment was found in the group with a shorter DUI (analysis of variance with repeated measures: time effect F=654.975, P<.001; group effect: F=4.369, P=.039). When computed with respect to the first treatment with benzodiazepines (DUI-BDZ), the two groups did not show any significant difference in treatment response (time effect: F=652.183, P<.001; group effect: F=0.009, P=.924). In addition, patients with a longer DUI (DUI-BDZ or DUI-AD) showed an earlier age at onset, a longer duration of illness and a higher rate of comorbid psychiatric disorders with onset later than GAD.

Conclusion: Results from this preliminary study seem to suggest that a shorter DUI-AD may determine a better response to pharmacologic treatment in patients with GAD, and that a longer DUI (DUI-BDZ and DUI-AD) may be associated to a worse clinical course. Further investigation on the relationship between DUI and GAD is needed.

May 7, 2008 - Coadministration of eszopiclone [Lunesta^®] and escitalopram [Lexapro^®] rapidly improved sleep and anxiety in patients with insomnia and generalized anxiety disorder, according to the results of a double-blind, randomized, placebo-controlled, parallel-group, add-on therapy, 10-week study reported in the May issue of the Archives of General Psychiatry.

WASHINGTON (AP) — Depression, teens and marijuana are a dangerous mix that can lead to dependency, mental illness or suicidal thoughts, according to a White House report being released Friday.

Malcolm Knox

An "internationally unique" treatment trial for dependent ice users is addressing new research showing that depression, more than psychosis, is the drug's most enduring consequence.

The pilot study at the National Drug and Alcohol Research Centre at the University of NSW is recruiting methamphetamine users who are suffering depression to put them through a program that researchers hope will lead to the world's first proven treatment for the drug.

da Silva Prado H, do Rosário MC, Lee J, Hounie AG, Shavitt RG, Miguel EC.

Department of Psychiatry, University of São Paulo Medical School, Brazil; Federal University of São Paulo, Brazil; Yale University School of Medicine, New Haven, Connecticut U.S.A.

Introduction: A variety of subjective experiences have been reported to be associated with the symptom expression of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). First described in TS patients, these subjective experiences have been defined in different ways. There is no consensus in the literature on how to best define subjective experiences. This lack of consensus may hinder the understanding of study results and prevents the possibility of including them in the search for etiological factors associated with OCD and TS.

Methods: The objective of this article was to review the descriptions of subjective experiences in the English-language literature from 1980-2007. This meta-analytic review was carried out using the English-language literature from 1980-2007 available on MEDLINE, PsycINFO, and the Cochrane Library databases using the following search terms: premonitory urges, sensory tics, "just-right" perceptions, sensory phenomena, sensory experiences, incompleteness, "not just-right" phenomena, obsessive-compulsive disorder and TS, including OCD and/or TS, in all combination searches. We also searched for the references cited in each article previously found that referred to the aforementioned terms. Thirty-one articles were included in the study.

Results: Subjective experiences, in particular, the sensory phenomena, were important phenotypic variables in the characterization of the tic-related OCD subtype and were more frequent in the early-onset OCD subtype. There is a paucity of studies using structured interviews to assess sensory phenomena, their epidemiology and the etiological mechanisms associated with sensory phenomena.

Conclusion: The current review provides some evidence that sensory phenomena can be useful to identify more homogenous subgroups of OCD and TS patients and should be included as important phenotypic variables in future clinical, genetic, neuroimaging, and treatment-response studies.