Bipolar Today

The genetics of fear

admin — Tue, 10 Mar 2009 23:01:48 +0000

Association for Psychological Science - Polymorphisms are variations in genes which can result in changes in the way a particular gene functions and thus may be associated with susceptibility to common diseases. In a new study in Psychological Science, a journal of the Association for Psychological Science, psychologist Tina B. Lonsdorf and her colleagues from the Karolinska Institutet in Sweden and the University of Greifswald in Germany examined the effect of specific polymorphisms on how fear is learned and how that fear is subsequently overcome.

Many symptoms of anxiety disorders are thought to be learned and research on fear conditioning (a method of learning to fear a particular stimulus) shows that individuals diagnosed with anxiety disorders are quick to learn to fear a stimulus but have a difficult time getting rid of that fear. In this study, the researchers focused on polymorphisms in two genes thought to play a role in anxiety disorders: the serotonin transporter gene and the gene for the enzyme COMT.

Serotonin is a brain chemical involved in mood regulation. The serotonin transporter, which is the target of selective serotonin reuptake inhibitors (SSRI) used to treat anxiety and depression, harbors a common polymorphism in its gene. This polymorphism can come in two different versions that differ in their length. The shorter version of the gene leads to less serotonin being cleared away and is also associated with higher neuroticism scores and anxious behavior. The COMT enzyme is involved in breaking down dopamine, a brain chemical important for learning, motivation and seeking rewards. A specific polymorphism in this gene results in higher levels of extracellular dopamine in the prefrontal cortex, leading to enhanced working memory but also greater levels of anxiety.

In this experiment, volunteers were shown a picture (A) and then immediately received a mild electric shock. They were also shown another picture (B) that was never associated with a shock. The participants learned during the experiment to fear picture A as assessed by physiological responses, the so-called fear potentiated startle response.

To test if this learned fear could be overcome (also known as fear extinction) the volunteers came back into the lab the following day. There they were shown the same pictures, but without any shocks. If their physiological fear responses disappeared, that meant that they had overcome their fear. In addition, blood samples were drawn from the volunteers and tested for the variants of the two genetic variations the researchers were studying.

The results showed that while the participants with the shorter version of the serotonin transporter gene developed a very strong physiological fear response to picture A, participants with a longer version of the gene did not. In addition, a variation in the gene coding for the COMT enzyme was associated with fear extinction - volunteers with this particular variant were able to very quickly overcome their fear while volunteers with the other variant failed to do so.

The researchers note that these findings have very interesting implications for understanding gene-environment interactions and that “genes may act through the environment by making carriers of particular gene combinations more likely than other individuals to easily pick up and retain fear of stimuli associated with threat and trauma.” The authors go on to suggest that these findings may indicate that individuals with specific polymorphisms may be more susceptible to anxiety disorders by being more prone to developing fear and being less likely to overcome that fear by common cognitive behavioral treatments which are based on the extinction principle.

Tags: anxiety disorder, genetics

New class of better antidepressants emerging

admin — Sat, 28 Feb 2009 14:12:13 +0000

Illustration by BP TODAY

Mayo Clinic news - Researchers at Mayo Clinic’s campus in Jacksonville and Virginia Tech in Blacksburg, Va., through their technology commercialization efforts, have licensed compounds to AstraZeneca for potential new drug therapies to treat depression. The collaboration advances both the development of novel compounds and supports ongoing research by Mayo and Virginia Tech in the area of triple reuptake inhibitors.

According to Elliott Richelson, M.D., Mayo Clinic Department of Pharmacology, this is important because triple reuptake inhibitors block reuptake of the neurotransmitters serotonin, norepinephrine, and dopamine. Certain antidepressants currently available for patients suffering from depression work by inhibiting or blocking serotonin reuptake. Others block both serotonin and norepinephrine reuptake. A key element in the way nerve cells work is when a neurotransmitter is released to relay its message, it returns to the nerve ending from which it was released. The mechanism of taking the neurotransmitter back into the nerve ending is called reuptake. In depression, there are fewer neurotransmitters being released in the brain. By blocking the reuptake of all three neurotransmitters more neurotransmitters can be sent to the nerve cells. Mayo’s collaboration focuses on a new class of antidepressants that block the reuptake of all three neurotransmitters.

The research leading up to this collaboration spans more than 10 years. Originally, Dr. Richelson was approached by chemist Paul Carlier, Ph.D., now at Virginia Tech, to collaborate in the discovery and evaluation of novel antidepressants. Dr. Carlier recognized Dr. Richelson’s unique expertise in psychiatric pharmacology combined with years of clinical practice treating patients with depression and anxiety.

Their efforts are fuelled by unmet needs in the treatment of depression. In particular, it can take weeks before antidepressants begin to relieve the signs and symptoms of depression. A large percentage of patients do not go into remission with initial treatment and may need to try a different antidepressant to go into remission. In addition, 10 to 15 percent of patients who have depression are considered treatment resistant. “There is hope that triple reuptake inhibitors can have a more rapid onset of action and can provide relief to a larger percentage of patients, including those who are considered treatment resistant,” says Dr. Richelson.

Triple reuptake inhibitors also should be more patient friendly, says Dr. Richelson. An existing class of drugs sometimes used for treatment-resistant depression is called monoamine oxidase inhibitors. These drugs also elevate synaptic levels of serotonin, norepinephrine, and dopamine. However, when taking monoamine oxidase inhibitors, patients need to avoid certain drugs and foods. “The likelihood of triple reuptake inhibitors reacting negatively to other medications seems small, and patients would not need to restrict food,” says Dr. Richelson.

According to Dr. Richelson, “The promise of this research collaboration is the development of new compounds to treat a range of psychiatric illnesses, in addition to depression. By better balancing the regulation of serotonin, dopamine, and norepinephrine reuptake, patients have a greater likelihood of successfully alleviating their psychological symptoms.”

Collaborators at Mayo, Virginia Tech and AstraZeneca are continuing to identify a variety of new compounds. The collaboration fulfills Mayo’s mission of meeting patient needs by taking Mayo research and discoveries to the global marketplace.

Tags: depression, triple reuptake inhibitors

Seroquel XR for bipolar launches

admin — Tue, 24 Feb 2009 10:48:15 +0000

AP - Drugmaker AstraZeneca PLC said Monday it launched its drug Seroquel XR as a treatment for bipolar disorder in addition to a previous approval for schizophrenia.

The London-based company will sell Seroquel XR as a treatment for depressive, manic and mixed episodes of bipolar I disorder, as well as schizophrenia in adults, and acute schizophrenic episodes. It can also be marketed in combination with two other commonly used depression treatments, lithium and divalproex.

Bipolar disorder is characterized by dramatic and severe mood swings.

The Food and Drug Administration approved Seroquel in bipolar disorder in late 2008. AstraZeneca said Seroquel XR is the only drug to get FDA approval in the bipolar disorder indications.

AstraZeneca also said it will market Seroquel XR in 50 mg and 150 mg strengths. The drug is currently on the market in 200 mg, 300 mg and 400 mg doses. Worldwide sales of Seroquel totaled $4.45 billion in 2008, making it AstraZeneca’s second-best selling drug after the heartburn treatment Nexium.

Tags: bipolar, Seroquel

New triple reuptake inhibiting drug invented

admin — Mon, 23 Feb 2009 12:21:15 +0000

Mayo Clinic release - Researchers at Mayo Clinic’s campus in Jacksonville and Virginia Tech in Blacksburg, Va., through their technology commercialization efforts, have licensed compounds to AstraZeneca for potential new drug therapies to treat depression. The collaboration advances both the development of novel compounds and supports ongoing research by Mayo and Virginia Tech in the area of triple reuptake inhibitors.

Their efforts are fueled by unmet needs in the treatment of depression. In particular, it can take weeks before antidepressants begin to relieve the signs and symptoms of depression. A large percentage of patients do not go into remission with initial treatment and may need to try a different antidepressant to go into remission. In addition, 10 to 15 percent of patients who have depression are considered treatment resistant. “There is hope that triple reuptake inhibitors can have a more rapid onset of action and can provide relief to a larger percentage of patients, including those who are considered treatment resistant,” says Dr. Richelson.

Tags: depression, triple reuptake inhibitor

Tricyclic antidepressants may induce mood conversions in bipolar

admin — Wed, 18 Feb 2009 12:14:02 +0000

BP TODAY - Tricyclic antidepressants may induce mood conversions in bipolar disorder, according to a new retropective study done in Poland.

The aim of this retrospective study was an analysis of antidepressant-induced mood conversions to mania/hypomania occurring in bipolar inpatients treated with antidepressants in the Affective Disorder Unit of the Institute of Psychiatry and Neurology, Warsaw, in the years 1972-1996.

Methods: The data for analysis were obtained retrospectively from clinical records. In a subgroup of patients prone to mood conversions, a comparison was done of depressive episodes treated with antidepressants with and without a switch to mania/hypomania as well as the frequency of mood conversions induced by particular antidepressant drugs, especially tricyclic (TCA) versus non-TCA drugs.

What are tricyclic antidepressants? Tricyclic antidepressants (TCAs) inhibit the reabsorption (reuptake) of serotonin and norepinephrine by brain cells. To a lesser extent, TCAs also inhibit reabsorption of dopamine. These antidepressants also block other cell receptors, which accounts for many of their side effects. TCAs are called tricyclic because of their chemical structure. They were among the earliest antidepressants developed and remained the first line of treatment for depression before newer antidepressants arrived.

Here are the TCAs approved by the Food and Drug Administration specifically to treat depression, with their generic, or chemical, names followed by available brand names in parentheses:

Amitriptyline

Amoxapine

Desipramine (Norpramin)

Doxepin (Sinequan)

Imipramine (Tofranil, Tofranil-PM)

Nortriptyline (Pamelor)

Protriptyline (Vivactil)

Trimipramine (Surmontil)

Some of these medications come in forms that must be injected or as oral solutions that must be mixed with liquids, such as water or juice.

Some of these medications may also be used to treat conditions other than depression.

Because TCAs are less selective about which cells they affect, they typically have more side effects than other antidepressants do.

Side effects of TCAs include:

Drowsiness

Dry mouth

Blurred vision

Constipation

Urinary retention

Dizziness

Impaired sexual functioning

Increased heart rate

Disorientation or confusion

Headache

Low blood pressure

Sensitivity to sunlight

Increased appetite

Weight gain

Nausea

Weakness

Results:

Among 333 bipolar patients hospitalized in this period, mood conversions were observed in 118 subjects (35%)

Mood conversions were significantly more frequently in female (44%) than in male patients (25%), and in patients with depressive episode at the onset of illness (80 vs. 40%).

Among mood converters, it was found that the depressive episodes with a switch to mania were less severe, shorter, and with shorter duration of antidepressant treatment.

The risk of switching was higher during treatment with TCA than with non-TCA drugs (36 vs. 17%), the highest with amitriptyline (42% of treated episodes), imipramine (40%) and clomipramine (35%).

Conclusions: The results suggest that bipolar patients prone to mood conversion constitute one third of the inpatient population with this illness. The switch from depression to mania occurred significantly more frequently during treatment with TCA than with non-TCA drugs.

It is hypothesized that anticholinergic activity may contribute to the higher frequency of TCA-induced mood conversions.

What is anticholinergic activity? Anticholinergic means blocking the effects of the neurotransmitter acetylcholine.

Acetylcholine is a neurotransmitter found in both the central nervous system and the peripheral nervous system. Acetylcholine plays an important role both in learning and memory and in sending messages from motor nerves to muscles, especially in the heart, bladder and stomach. It also affects glands. There is a marked deficiency of acetylcholine in the brains of patients with Alzheimer’s Disease. Drugs with anticholinergic effects target acetylcholine receptors.

Drugs that have anticholinergic effects include but are not limited to:

Tricyclic antidepressants

Antipsychotics

SSRI antidepressants Prozac, Zoloft and Paxil

Diphenhydramine (Benadryl, other generic antihistamines)

[Neuropsychobiology. 2009 Feb 17;59(1):12-16.]

Tags: bipolar, depression, mood, Tricyclic antidepressants

Thyroid hormone gives hope to treatment-resistant bipolar, depression

admin — Tue, 17 Feb 2009 16:06:57 +0000

BP TODAY - Thyroid hormone triiodothyronine (T3) may help hard-to-treat patients with bipolar disorder and depression, as an augmentation agent in existing treatments, a new study says.

Digital image of serentonin Molecular Expressions (http://micro.magnet.fsu.edu)

The study was carried out by scientists at the Depression & Bipolar Clinic of Colorado. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS was tested.

(To learn more about types of bipolar disorders please check our Glossary).

BACKGROUND: Thyroid hormone plays a role in both serotonin and catecholamine functions in the brain, and has been linked to abnormal mood states in bipolar disorder.

Unlike most studies which have included only patients with bipolar I, this study evaluated triiodothyronine (T3) as an augmentation agent for treatment-resistant depression in patients with bipolar II and bipolar disorder NOS.

METHODS: This study was a retrospective chart review of patients treated in a private clinic between 2002 and 2006. The charts of 125 patients with bipolar II disorder and 34 patients with bipolar disorder NOS were reviewed.

RESULTS: Patients had been unsuccessfully treated with an average of 14 other medications before starting T3. At an average dose of 90.4 mcg (range 13 mcg-188 mcg) the medication was well tolerated. None of the patients experienced a switch into hypomania, and only 16 discontinued due to side effects. Improvement was experienced by 84%, and 33% experienced full remission.

LIMITATIONS: The limitations are those associated with the retrospective chart review design.

CONCLUSIONS: A high percentage of bipolar II and bipolar NOS patients with treatment resistant depression improved on T3. Despite the use of higher than usual doses in many of the patients, the medication was well tolerated. Augmentation with supraphysiologic doses of T3 should be considered in cases of treatment resistant bipolar depression.

[J Affect Disord. 2009 Feb 10.]

Tags: bipolar, catecholamine, depression, serotonin, thyroid hormone

8 risk factors for suicide attempts of bipolar patients identified

admin — Tue, 17 Feb 2009 09:37:26 +0000

Illustration by BP TODAY

BP TODAY - A team of French scientists have identified 8 risk factors associated with lifetime suicide attempts of bipolar patients from a France national cohort.

Risk factors that may be associated with suicide attempts in bipolar disorder are still a matter of debate. The researchers compared demographic, illness course, clinical, and temperamental features of suicide attempters vs those of nonattempters in a large sample of bipolar I patients admitted for an index manic episode.

The research was carried out at the Department of Psychiatry of the Sainte Marguerite Hospital in France.

1090 patients (attempters = 382, nonattempters = 708) were included in the study.

Multivariate analysis evidenced 8 risk factors associated with lifetime suicide attempts as follows:

multiple hospitalization
depressive or mixed polarity of first episode
presence of stressful life events before illness onset
younger age at onset
no free intervals between episodes
female sex
higher number of previous episodes
cyclothymic temperament

What is Cyclothymic Personality Disorder? Cyclothymic Personality Disorder is a pervasive pattern of pronounced periodic changes in mood, behavior, thinking, sleep, and energy levels, beginning by early adulthood and present in a variety of contexts, as indicated by seven (or more) of the following:

has depressive periods: depressed mood or loss of interest or pleasure in all, or almost all, activities and pastimes alternating with hypomanic periods: elevated, expansive, or irritable mood (American Psychiatric Association, 1980, pg. 220);

becomes excessively involved in pleasurable activities with lack of concern for the high potential of painful consequences alternating with restriction of involvement in pleasurable activities and guilt over past activities (pg. 220);

alternates between over-optimism or exaggeration of past achievement and a pessimistic attitude toward the future, or brooding about past events (pg. 220);

is more talkative than usual, with inappropriate laughing, joking, and punning: and, then, less talkative, with tearfulness or crying (pg. 220);

has a decreased need for sleep alternating with hypersomnia (Akiskal, Khani, and Scott-Strauss qtd. in Jamison, pg. 264); 1

has shaky self-esteem: naive grandiose overconfidence alternating with lack of self-confidence (pg. 264);

has periods of sharpened and creative thinking alternating with periods of mental confusion and apathy (pg. 264);

displays marked unevenness in the quantity and quality of productivity, often associated with unusual working hours (pg. 264);

engages in uninhibited people-seeking (that may lead to hyper-sexuality) alternating with introverted self-absorption (pg. 264);

frequently shifts line of work, study, interest, or future plans (pg. 264);

engages in occasional financial extravagance (pg. 264);

has a tendency toward promiscuity, with repeated conjugal or romantic failure (pg. 264);

may use alcohol or drugs to control moods or to augment excitement (pg. 264);

has irritable-angry-explosive outbursts that alienate loved ones (pg. 264);

makes frequent changes in residence or geographical location (Akiskal, 1995, pg. 1143).

These characteristics may help identify subjects at risk for suicide attempt throughout the course of bipolar disorder. The scientists propose to integrate such characteristics into a stress-diathesis model of suicidal behaviour, adapted to bipolar patients.

[Compr Psychiatry. 2009 March - April;50(2):115-120. Epub 2008 Sep 20.]

Tags: bipolar, risk factors, suicide

Blood pressure pill may ‘erase’ bad memories

admin — Tue, 17 Feb 2009 08:28:10 +0000

Reuters - A widely available blood pressure pill could one day help people erase bad memories, perhaps treating some anxiety disorders and phobias, according to a Dutch study published on Nature Neuroscience.

The generic beta-blocker propranolol significantly weakened people’s fearful memories of spiders among a group of healthy volunteers who took it, said Merel Kindt, a psychologist at the University of Amsterdam, who led the study.

“We could show that the fear response went away, which suggests the memory was weakened,” Kindt said in a telephone interview.

The findings published in the journal Nature Neuroscience are important because the drug may offer another way to help people suffering from post-traumatic stress disorder and other problems related to bad memories.

Traditionally, therapists seek to teach people with such disorders strategies to build new associations and block bad memories. The problem, Kindt said, is the memories remain and people often relapse.

Animal studies have shown that fear memories can change when recalled, a process known as reconsolidation. At this stage they are also vulnerable to beta-blockers like propranolol, which target neurons in the brain, the researchers said.

Kindt and her team’s experiment included 60 men and women who learned to associate pictures of spiders with a mild shock. This experience created a fearful memory, the researchers said.

Other participants saw the same picture but did not receive an electrical shock. For these people this established a “safe” association without a fear response or bad memory.

One day later people given the drug had a greatly decreased fear response compared with people on the placebo when shown the picture and given a mild shock, the researchers said.

“There was no difference to the fear spider and the safe spider,” Kindt said. “This shows it is possible to weaken the underlying memory by interfering with it.”

The next steps are to look at how long the drug’s effects on memory last, and testing the treatment in people who actually are suffering from some kind of disorder or phobia, Kindt said.

Tags: brain, memory

Bipolar ups risk of early death

admin — Tue, 17 Feb 2009 05:31:39 +0000

UPI - Bipolar disorder, like smoking, increases the risk of early death from medical illnesses, a U.S. review found.

The review of 17 studies, published in Psychiatric Services, involving more than 331,000 patients suggested that people with bipolar disorder have a higher mortality from natural causes compared with people in the general population of similar age and gender but without mental illness.

“The review of data gathered from large population studies suggests that having bipolar disorder is similar to being a smoker in terms of increasing a person’s risk of early death,” Dr. Wayne Katon of the University of Washington in Seattle, co-author of the review, said in a statement.

People with bipolar disorder tend to have both manic phases that can include sleepless periods and depressed phases that can even leave them immobilized. There are many possible factors that may account for the higher risk of premature death.

Katon says psychiatrists and other mental health workers need to be trained to monitor their patients’ basic physical health and learn how to advise patients to exercise, quit smoking or to take other illness prevention measures.

“Changes are also occurring in medical schools to teach new physicians in all specialties how to recognize psychiatric illnesses and to understand the serious health risks associated with mental illness,” Katon said.

Tags: bipolar, death

Research finds link between brain and loneliness

admin — Tue, 17 Feb 2009 03:16:58 +0000

Social isolation affects how people behave as well as how their brains operate, a study at the University of Chicago shows.

The research, presented Sunday at a symposium, “Social Emotion and the Brain,” at the annual meeting of the American Association for the Advancement of Science, is the first to use fMRI scans to study the connections between perceived social isolation (or loneliness) and activity in the brain. Combining fMRI scans with data relevant to social behavior is part of an emerging field examining brain mechanisms—an approach to psychology being pioneered at the University of Chicago.

Researchers found that the ventral striatum—a region of the brain associated with rewards—is much more activated in

non-lonely people than in the lonely when they view pictures of people in pleasant settings. In contrast, the temporoparietal junction—a region associated with taking the perspective of another person—is much less activated among lonely than in the non-lonely when viewing pictures of people in unpleasant settings.

“Given their feelings of social isolation, lonely individuals may be left to find relative comfort in nonsocial rewards,” said John Cacioppo, the Tiffany and Margaret Blake Professor in Psychology at the University. He spoke at the briefing along with Jean Decety, the Irving B. Harris Professor in Psychology and Psychiatry at the University.

The ventral striatum, which is critical to learning, is a key portion of the brain and is activated through primary rewards such as food and secondary rewards such as money. Social rewards and feelings of love also may activate the region.

Cacioppo, one of the nation’s leading scholars on loneliness, has shown that loneliness undermines health and can be as detrimental as smoking. About one in five Americans experience loneliness, he said. Decety is one of the nation’s leading researchers to use fMRI scans to explore empathy.

They were among five co-authors of a paper, “In the Eye of the Beholder: Individual Differences in Perceived Social Isolation Predict Regional Brain Activation to Social Stimuli,” published in the current issue of the Journal of Cognitive Neuroscience.

In the study, 23 female undergraduates were tested to determine their level of loneliness. While in an fMRI scanner, the subjects were shown unpleasant pictures and human conflict as well as pleasant things such as money and happy people.

The subjects who rated as lonely were least likely to have strong activity in their ventral striata when shown pictures of people enjoying themselves.

Although loneliness may be influence brain activity, the research also suggests that activity in the ventral striatum may prompt feelings of loneliness, Decety said. “The study raises the intriguing possibility that loneliness may result from reduced reward-related activity in the ventral striatum in response to social rewards.”

In addition to differing responses in the ventral striatum, the subjects also recorded differing responses in parts of the brain that indicated loneliness played a role in how their brain operates.

Joining Decety and Cacioppo in writing the Journal of Cognitive Science paper were Catherine Norris, Assistant Professor of Psychology at Dartmouth College; George Monteleone, a graduate student at the University of Chicago; and Howard Nusbaum, Chair of Psychology at the University of Chicago.

Decety and Cacioppo discussed the new field of brain mechanism in a paper in the current issue of Perspectives on Psychological Science, “What Are the Brain Mechanisms on Which Psychological Processes are Based?” The new field extends the work of Charles Darwin, who “regarded the brain as a product of evolution and the science of psychology as concerned with these foundations,” they wrote.

By studying brain mechanisms, researchers hope to gain new insights by examining mental activities surrounding consciousness, perception and thought through an understanding of how columns of neurons stacked next to each other form elementary circuits to function as a unit, they wrote.

New visualization tools such as three-dimensional imaging will help scholars develop a new way of studying psychology, they said.

“Psychological science in the 21st century can, and should, become not only the science of overt behavior, and not only the science of the mind, but also the science of the brain,” they concluded.

Source

Tags: brain, lonely

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