Drug Prozac

Headway in developing a faster-acting antidepressant

August 30, 2007

After years of little progress, scientists are making headway in the search for a better, faster-acting antidepressant. Experiments with an anesthetic called ketamine have yielded important clues about the biology of depression, leading scientists to attack the mood disorder in new ways.

Improved treatments are sorely needed. Depression affects about one in 10 adult Americans each year, while current drugs work in only 50% to 60% of patients, can cause sexual problems and take weeks to work. They also carry a small risk of suicidal thoughts and behaviors in adolescents and young adults.

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FOR THE RECORD:
Ketamine: An Aug. 27 Health section article on the search for new antidepressants said the amino acid glutamine has a role in depression. It is glutamate, a related amino acid that acts as a neurotransmitter in the brain, that has a role in depression. —

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All existing antidepressant drugs work in much the same manner. They act on a handful of neurotransmitters — brain chemicals that pass messages along defined pathways — that belong to a family called monoamines and circulate in a relatively small portion of the brain.

The most recognized of these neurotransmitters is serotonin, low levels of which have been linked to depression. Drugs such as Prozac and Celexa are aimed at raising serotonin levels available to the brain. The other transmitters targeted by antidepressants are dopamine and norepinephrine. Wellbutrin is an example of an antidepressant that boosts levels of these neurotransmitters but not serotonin.

Scientists first discovered these neurotransmitters affect depression in the 1950s when they found that the tuberculosis drug iproniazid also lifted patients’ moods. The drug blocks an enzyme that converted serotonin, dopamine and norepinephrine into inactive forms, and after some study the drug was marketed for depression. Pharmaceutical companies have developed drugs targeting the trio of neurotransmitters ever since.

Because it is expensive to discover and develop new drugs, it is safer for pharmaceutical companies to stick with known biological targets than to head in risky new directions, said Dr. Carlos Zarate Jr., a researcher at the National Institute of Mental Health. As a result, “we have not made substantial gains in terms of antidepressants,” Zarate said.

But recent studies on ketamine have pushed researchers to change how they think about depression. The anesthetic acts on glutamate, the brain’s most plentiful neurotransmitter, which circulates widely in the brain and hasn’t been linked to depression in the past.Discount Pharmacy - Buy Pharmacy at discount prices including free shipping.Discount Pharmacy provides confortable and easy way to order discount pharmacy online.

In a small experiment led by Zarate last year, five of 18 people who received a single intravenous dose of ketamine experienced a dramatic lifting of their depression the first day and were still much better a week later. All patients in the experiment had first tried regular antidepressants but did not improve on them, according to the study published last August in the Archives of General Psychiatry.

Similar fast improvements were found in a study of eight patients conducted at Yale Medical School and published in Biological Psychiatry in 2000.

The rapid response was encouraging, Zarate said, suggesting that a faster-acting antidepressant may be possible. Current antidepressants take two to three weeks to begin working, and until recently, “it was just accepted as fact we couldn’t do any better,” he said.

Dr. Gerard Sanacora, director of the depression research program at Yale Medical School, said the results also mean that glutamate may have a more direct role in depression than serotonin and other brain chemicals targeted by current antidepressants.

“The fact that it acts so rapidly means that it is getting closer to the core of depression,” Sanacora said.

In some ways, it’s surprising that researchers studying depression didn’t suspect the role of glutamate, which is an amino acid, in the disorder sooner. Malfunctions in the glutamate system have long been linked to other psychological and neurological disorders, including schizophrenia and Alzheimer’s disease. Glutamate has long been associated with learning and memory.

“It is hard to image anything glutamate is not involved in,” said Sanacora. “It is really what makes the brain run.”

Still, scientists haven’t yet figured out how the glutamate system goes awry in depression.

One theory is that glutamate leaks from brain cells, perhaps in response to chronic emotional stress, and causes changes in key brain structures.

The hippocampus, which processes memory, and the parts of the cortex, where decisions are made, are known to be smaller in depressed people. Perhaps, Zarate said, excess glutamate caused cells in these brain structures to shrivel. High amounts of glutamate are toxic to brain cells and cause the death of some neurons in stroke patients, he noted.

Ketamine is not approved for treating depression and Zarate said it was too soon to give it to patients outside the confines of a clinical trial.

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High-yielding Biovail races clock to get new product in pipeline

August 26, 2007

Late last year, Biovail Corp. dressed up its dividend to buy its stock some time. Now, eight months later and with its pipeline for new products clogged by regulatory delays, that time could run out, analysts say.

With full generic competition for the company’s flagship Wellbutrin XL antidepressant coming some time next year, analysts wonder whether Biovail will be able to maintain its generous dividend payments, which were tripled to an annual rate of $1.50 (U.S.) a share last December. The dividend, which generates a yield of about 9 per cent at the current stock price, has become the main attraction to the stock while investors await new products to replace the anticipated deep declines in revenue and cash flow from Wellbutrin.

“Biovail’s value is being supported by the dividend, which we believe is unsustainable,” analyst Anthony Scilipoti of Veritas Investment Research Corp. said in a recent report.

“Armed with one drug, a stable of declining generics and legacy product lines, the company will be hard pressed to maintain its dividend past the end of 2007.”

The prediction is simple arithmetic. Biovail will pay out about $240-million this year in dividends, which amounts to a generous 86 per cent of projected distributable cash (cash flow after capital expenditures). But Mr. Scilipoti projects that full generic competition could reduce Wellbutrin XL’s cash flow contribution by more than $150-million, leaving Biovail without enough cash generation to cover the dividend payments next year.

“Unless a new golden goose is found, [2008 operating cash flow] will be 30 per cent lower than [2007 estimates],” he said, adding that based on the current operating model, “Biovail will be short roughly $60-million to pay its dividend.”

That new golden goose was expected to be a new antidepressant that Biovail had hoped to launch before the end of this year. But last month the U.S. Food and Drug Administration (FDA) rejected one of the company’s studies for a once-a-day formulation of bupropion, a key component of the new product - potentially setting back the launch by as much as a year.

The news wiped out 20 per cent of Biovail’s stock value in a single day. Since then, the stock has continued to slide, closing at $18.28 (Canadian) on the Toronto Stock Exchange yesterday, down 31 per cent from its levels before the FDA announcement.

For many investors, last December’s dividend increase was seen as a stop-gap measure to keep them interested in the stock during a lull in Biovail’s product pipeline, temporarily converting the stock into a yield play until new products could come on line and return the stock to its more traditional profile as a growth play. Indeed, Biovail spokesman Nelson Isabel said the company expects to have “10 major development projects under way” by the end of this year.

But the question, in light of the FDA news, is how far away those prospects are - and whether the dividend can survive the wait.

First Albany Capital analyst David Lickrish said last year’s dividend increase “was actually quite a clever idea,” succeeding in lifting Biovail’s stock in the first half of this year even as sales and earnings shrunk. But now, with the new-product outlook clouded and investors relying increasingly on the dividend, “they’ve painted themselves into a corner.”

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Biovail stated shortly after the FDA announcement that it had no intention of cutting its dividend - a position Mr. Isabel reiterated yesterday.

“As investors begin to appreciate what’s in the pipeline … I think they will begin to have confidence in what we have and in the growth of the company,” chief executive officer Douglas Squires said recently.

Mr. Lickrish added that the company remains optimistic that it can clear the FDA hurdles for its new antidepressant before Wellbutrin becomes fully open to generic competition some time next year.

A major institutional shareholder of the stock noted that the company does have roughly $500-million of cash on hand to bolster its payments if cash flow does fall short of covering the dividend payout.

Mr. Scilipoti said Biovail might be able to reduce R&D spending to free up cash, and it has enough cash and unused credit lines to finance a modest-sized acquisition that could generate additional cash flow. But both of those strategies would go against the strategic focus management adopted last December, geared to developing and manufacturing new home-grown products.

Biovail’s Mr. Isabel said the company is “actively evaluating” several possible acquisitions “of all sizes,” but declined to elaborate.

The dividend and new-product question marks, coupled with continuing regulatory investigations into Biovail’s accounting practices in the early part of this decade, have depressed the company’s stock valuation. Biovail is trading at under 10 times its forward 12-month earnings estimates - compared with better than 18 times for the S&P/TSX health care subindex as a group.

That does present a buying opportunity for anyone patient enough to see if the company’s growth story can return.

“The problems the company has had and the negative press it has received have created a stock that is quite undervalued,” the institutional investor said. “There’s an opportunity for value creation here.”

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Adolescent Suicides Are On the Rise

August 23, 2007

Suicide is the eighth leading cause of death for all persons regardless of age, sex or race; the third leading cause of death for young people aged 15 to 24; and the fourth leading cause of death for persons between the ages of 10 and 14. The rates of youth suicide had been declining since 1994, but the numbers are rising dramatically. Are the good intentions of the FDA to blame?

Each year, there are approximately 12 suicides for every 100,000 adolescents. A recent CDC study reported that 27% of high school students said they had thought seriously about killing themselves during the past year. 8% said they had actually tried to kill themselves.

Although suicide is considered the most preventable cause of death, not all suicides are preventable. It is inevitable that all law enforcement officers will be called to the scene of a completed suicide. Welfare check calls related to a subject’s suicide risk are routine. After working as a psychiatric nurse for well over two decades, I have learned there are two types of therapists: those who have lost a client to suicide and those who will. It just feels different when it is a kid.

What to Look For

Nine out of ten adolescents who commit suicide give clues before the suicide attempt. Most teenagers will display one or more of the following risk factors and/or warning signs:

• A mental health disorder such as depression; alcohol or substance abuse; or behavior/conduct disorders (chronic runaways, incarcerations). A combination of any of these increases the risk.
• Communication of thoughts of suicide, death, dying, reunion with the dead
• Expression of sadness, boredom, negativity
• Impulsivity, aggression, frequent rage
• Exposure to someone else’s completed or attempted suicide
• Giving away prized possessions; making a will
• A recent severe stressor (pregnancy, sexual orientation issues, loss of a relationship, a significant failure)

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• Family instability/conflict
• An effort to punish oneself or others –the ultimate revenge
• Undue shame or guilt
• A victim or perpetrator of sexual, physical or emotional abuse
• Accessibility to lethal methods, especially guns

For a teen, suicide is viewed as a way to escape from an uncomfortable situation, emotional pain or unacceptable feelings. Most adolescent suicide attempts are precipitated by interpersonal conflicts; the intent is often not to kill themselves, but to change the behaviors or attitudes of others. It gives a teen a sense of control, when they feel out of control with the rest of their world. Most adolescent suicides occur in the teen’s home, after school hours.

Compared to adults, adolescent suicides are often more impulsive, related to anger or irritation, romantically or idealistically driven, and motivated by revenge. Attempts may indeed be manipulative, but only a professional psychiatrist or clinician should make that determination.

Treatment: Therapy, Medication (and the Black Box)

Thoughts of suicide span a lifetime; they are very common. These thoughts may be in relation to a situational crisis, or they may be the hallmark of a mental illness. Anytime anyone verbalizes suicidal intent, they should be referred to a mental health professional. Treatment typically includes psychotropic medications and therapy. When a child or teen has a mild depression, the first line of treatment is therapy: individual, behavioral, cognitive, group and/or family. When the depression is moderate to severe, a psychiatrist may prescribe an antidepressant. Currently only Prozac, a SSRI (selective serotonin reuptake inhibitor) antidepressant, is FDA approved to treat depression in children and adolescents. Additionally, Prozac and three other antidepressants have been FDA approved for pediatric obsession compulsive disorder: Zoloft, Anafranil, and Luvox.

Suicide rates for adolescents declined from 1994-2003, but increased 18% the following year. This increase coincided with the publicity of research (recently determined to be contradictory at best, and essentially flawed at worst) related to an increased suicide risk between antidepressant treatment and suicide risk in children and adolescents. In 2004, these concerns resulted in a FDA black box warning:

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Prenatal antidepressants linked to preterm births

August 18, 2007

Antidepressant drug use during pregnancy, but not depression itself, is associated with an increased risk of preterm birth and lower fetal age at delivery, according to results of a study published in the American Journal of Psychiatry.”Depressive symptoms are not uncommon during pregnancy, and…symptoms may occur more frequently during pregnancy than in the postpartum period,” write Dr. Rita Suri and colleagues from the University of California, Los Angeles. Depression during pregnancy and just after delivery “has been associated with low maternal weight gain, increased frequency of cigarette, alcohol, and substance use, and ambivalence about the pregnancy.”

To further investigate, the researchers examined the effects of maternal depression and antidepressant drug use on fetal age and risk of preterm birth in a study of 90 pregnant women.

The women were divided into three groups: 49 women had major depressive disorder and were treated with antidepressant medication for more than 50 percent of their pregnancy; 22 women had major depressive disorder and were briefly treated or not treated with antidepressants during pregnancy; and a comparison group of 19 healthy pregnant women.

Discount Pharmacy - Buy Pharmacy at discount prices including free shipping.Discount Pharmacy provides confortable and easy way to order discount pharmacy online.The average fetal age at birth was 38.5, 39.4, and 39.7 weeks in the three groups, respectively. The groups also differed in the rates of preterm birth (14.3 percent, 0 percent, and 5.3 percent) and rates of admission to the special care nursery (21 percent, 9 percent, and 0 percent).

No significant between-group differences were observed in actual infant birth weights or Apgar scores.

Based on these findings, the presence of depression per se during pregnancy did not adversely affect outcomes. “This result was surprising to us, as we had anticipated that depression and anxiety during pregnancy would be associated with an increased risk of preterm birth,” Suri and colleagues write.

“The two groups of women with depression — those who were treated with antidepressants and those who were not — had similar degrees of depression and anxiety during pregnancy,” they note.

These findings suggest that antidepressant use, rather than mild-to-moderate depression, was associated with lower fetal age and an increased risk of preterm birth.

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How antidepressant drugs work as roadblocks for brain chemicals

August 10, 2007

The way in which antidepressants exert their effects on brain cells has been revealed by two separate teams of researchers working independently of each other.

Antidepressants work by preventing neurons in the brain from importing certain chemicals, such as dopamine and serotonin, which are used to pass messages from cell to cell. The route by which these chemicals are imported depends on passageways in the outer membrane of the cells called transporter proteins, and it is on these passageways that the antidepressants exert their influence. But how exactly they hold up the process has remained a mystery since the drugs were discovered 45 years ago, says Les Iversen, a pharmacologist at the University of Oxford, UK.

To resolve the mystery, both teams — one led by Eric Gouaux of Oregon Health and Science University in Portland and the other based at New York University and led by Da-Neng Wang — set out to understand what happens when antidepressants lock onto a transporter at the most fundamental level. They zoomed in on the transporters’ molecular structures as revealed at atomic resolution through X-ray crystallography.

The researchers couldn’t use human transporter proteins because they are difficult to isolate and fall apart easily. Instead they used an equivalent found in bacteria called LeuT. They then selected drugs from a class called tricyclic antidepressants and created crystals in which the drug and the transporter were bound together. Gouaux’s team used a drug called clomipramine while Wang’s used a similar compound called desipramine.

Their results provide the first glimpse of the mechanism by which the drugs block the transporters. Both groups agree on what’s happening: the drug binds to the outside of the transporter, changing its shape. This traps the brain chemical inside the tunnel like a cork in a bottle, preventing it from passing through to the inside of the neuron. They published their results almost simultaneously in Nature¹ and Science² this week.

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Drug traps

“We now have our mind around the problem,” says Gouaux, whose team focused on working out exactly how the drug traps and holds the chemical inside the transporter. Now that we understand the basic movements, he says, “we’re in a much more powerful position to design molecules to inhibit it”.

Wang and his team wanted to look at how easy it would be to generalize the results they got in bacteria to humans. To design better drugs for depression, Wang says, “eventually we’ll need to work on the human protein”. So his group created mutations in the genetic sequence of some human versions of the protein, and then watched what happened when they added desipramine.

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Wang and his colleagues knew from their studies of LeuT which part of the protein the drug bound to. And when they mutated the same part in human versions of the protein, they found that the drug didn’t stop cells taking in dopamine or serotonin, suggesting that it could not block the transporters on which its binding site had been modified as efficiently as it does the normal transporters. “We basically proved that the inhibitory mechanism and binding site is conserved in humans,” Wang says.

But although Iversen describes the studies as “elegant science”, he is sceptical about how useful they will be when it comes to creating new drugs for depression. Information about structure hasn’t yielded fruit so far, and drugs have been developed without it. “I don’t think we really need to know this,” he says. “Drug discovery people have been studying these binding sites without knowing where they are.”

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Gene predicts antidepressant success

August 7, 2007

Scientists have found a second gene that helps predict whether people with depression will respond to a commonly prescribed anti-depressant, US researchers say.

On its own, the gene variation plays only a small role in predicting a patient’s response to Forest Laboratories Inc’s Celexa, known generically as citalopram.

But when a patient also had a variation of another gene, they were 23 per cent more likely to benefit, according to the study which appears in the American Journal of Psychiatry.

The finding may one day give doctors a better shot at choosing the right anti-depressant for the right patient, helping to eliminate the trial and error process many people undergo before they find an effective treatment.

“This is definitely a step ahead,” said Dr Gonzalo Laje, a researcher at the National Institute of Mental Health, in a telephone interview.

He said depression will be the second-leading cause of disability by the year 2020.

“It’s huge. It costs the US over $US43 billion ($A51 billion) every year in terms of direct and indirect medical costs.”

“If we can identify markers that would predict who gets better with which treatment, we can maybe decrease this burden and make the disease easier to treat,” Laje said.

He said researchers will need to identify more markers before the research will be of use, but it helps scientists better understand the disease and gives a clearer picture of who might benefit.

Ideally, Laje would like to be able to find enough gene variants to predict when a patient is 95 per cent more likely to benefit.

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Researchers studied DNA samples collected in the $US35 million ($A41 million), seven-year Sequenced Treatment Alternatives to Relative Depression, or STAR*D, a study paid for by the National Institute of Mental Health.

Earlier findings from this study found Celexa sent 37 per cent of patients who took it into remission.

In the latest study, researchers examined genetic material from 1,816 patients, comparing data from those who responded to Celexa and those who didn’t.

They found people with a variation in the GRIK4 gene were more likely to respond to the drug, especially when they also had a variation of the HTR2A gene.

Prior studies have shown variations in the HTR2A gene - which makes a protein related to the chemical messenger serotonin - play a role in a patient’s response to Celexa.

The GRIK4 gene makes a protein that is involved with the glutamate system, which also has been linked with depression.

Researchers said the findings are building a better picture of the biological mechanisms that underlie depression, a disease that affects about 121 million people worldwide, according to the World Health Organisation.

In the United States, an estimated 21 million adults, or 9.5 per cent of the population, have depression at some point. It is the leading cause of suicide.

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Antenatal Depression: Navigating the Treatment Dilemmas

August 2, 2007

“Ms. A” was a 35-year-old married Caucasian health care professional with a history of recurrent major depressive disorder that responded well to treatment with a selective serotonin reuptake inhibitor (SSRI). She discontinued her antidepressant prior to conception for a planned pregnancy because she did not want to expose her baby to medication. She soon relapsed, and by the first trimester of her pregnancy, she was in a major depressive episode. Her symptoms included anhedonia, tearfulness, irritability, insomnia, and diminished appetite. She presented for participation in an open-label pilot trial of omega-3 fatty acids for antenatal major depressive disorder (1). At intake, after hearing the risks and benefits of available treatment options, Ms. A declined antidepressant medication and a referral for psychotherapy and consented to participate in the study of omega-3 fatty acids, which she started at 16 weeks’ gestation. She was assessed every 2 weeks throughout pregnancy. At 8 weeks she had not responded to omega-3 fatty acids and was again presented with other treatment options, including medication and psychotherapy. She again declined these treatments and continued to do so throughout the remainder of her pregnancy. She was concerned about the safety of medications in pregnancy and believed that taking medication would make her a bad mother. She also declined referral for psychotherapy, stating that she was “too busy.”

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“Ms. B” was a 24-year-old married Hispanic woman with a 2-year-old son. She presented 20 weeks into a planned pregnancy. She had been looking forward to having a second child until the onset of a major depressive episode. While undergoing routine obstetrical screenings, she found herself hoping that testing would reveal fetal abnormalities so that she would have an excuse to end the pregnancy. However, screening and amniocentesis (after a false positive elevated maternal serum alpha-fetoprotein level) revealed no such abnormalities. She felt too depressed to imagine how the baby would be incorporated into her family and noted that she did not feel excitement about the baby. She was anhedonic and socially withdrawn. She had intermittent suicidal thoughts but stated that she would never harm herself because of her religious beliefs. Among her numerous psychosocial stressors was that her husband had recently started a new job that required him to move to another city, which meant that they were together only on weekends. Her functioning at work and as a mother was impaired by her depressive symptoms. Treatment options and the associated risks and benefits were explained to her. In the midst of the discussion about the risks and benefits of SSRIs, Ms. B stated, “I hear what you are saying, but I just want to feel better as soon as possible. I cannot think about the risks to the baby.”

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Review of Precautions of Antidepressant Therapy

July 29, 2007

Antidepressants are useful in the treatment of various conditions, including mood disorders, anxiety disorders, eating disorders, impulse control disorders, and aggression. However, antidepressants are not without limitations and precautions. This article addresses the more serious problems to consider when using antidepressants to treat patients for psychiatric disorders.
Suicidality
Concern exists about an association between suicidality and antidepressant use. All antidepressants presently bear a black box warning from the US Food and Drug Administration (FDA) about suicidality in children and adolescents. The association is controversial, with paroxetine (Paxil) currently at the center of the controversy. In 2001, a United States District Court held “there was sufficient evidence to support finding that homicides and suicide were caused by Paxil” and denied a motion for a new trial.1

A study of 1,191 children and adolescents found that suicide-related events were significantly more frequent with paroxetine than with placebo, with all but one event occurring in children aged at least 12 years.2 A recent meta-analysis, which used a Bayesian technique, found a strong association between paroxetine and suicidality.3 A cross-sectional survey with a cohort analysis of 1,000 patients with bipolar disorder who were studied under naturalistic conditions for at least one year found no association between paroxetine and suicidality in those aged 21 years or younger. The study actually found a trend of decreased suicidality in youths.4 In another view of this issue, toxicology testing performed in New York City from 1993-1998 on individuals aged less than 18 years who committed suicide revealed no paroxetine use and rarely any antidepressant use immediately prior to suicide.5 Another study of 159,810 patients taking antidepressants found that the risk of suicidal behavior in patients aged 10-19 years is not substantially different among those taking amitriptyline, fluoxetine, and paroxetine.6 However, the risk of suicide was increased during the first month of treatment, particularly during the first 9 days, in this same study.6

A study of 15,390 patients with depression (mean follow-up, 3.4 years) found the lowest risk of suicide with fluoxetine and the highest risk with venlafaxine.7 Curiously, overall mortality was lower with selective serotonin reuptake inhibitor (SSRI) use; this was attributed to decreased rates of cardiovascular- and cerebrovascular-related deaths.7

Every psychiatric patient should be evaluated for suicidality. The risk factors for suicidality include a history of suicide attempts, bipolar disorder, depression, severe anxiety, personality disorder, substance abuse, a first-degree relative who committed suicide, akathisia, and the spring season. Ways to reduce the risk of suicide include therapeutic rapport, limiting quantities of medications, frequent visits (particularly during the first 2 weeks of treatment), and psychosocial support. Anecdotally, no-harm contracts have prevented several of the author’s patients from attempting suicide.

BIPOLAR DEPRESSION AND INDUCTION OF HYPOMANIA AND MANIA
Bipolar disorder has a community prevalence of 3.7% in the United States.8 Bipolar spectrum disorders (BSD) are diagnostic challenges for several reasons. Depressive episodes in BSD last 3 times longer than manic episodes. Accordingly, approximately 80% of patients with BSD present with depressive episodes. Not surprisingly, clinicians often misdiagnose BSD.9 The consequences of misdiagnosis can include loss of employment, excessive use of health care services, impaired relationships, and an overall disturbed quality of life. Compared with patients with schizophrenia and major depression, patients with BSD have equally high or higher levels of impairment and disability.10

A thorough history and mental status examination are the criterion standards to diagnose BSD. Risk factors for bipolar disorder include symptom onset between 18 and 27 years of age, family history of bipolar disorder, 3 generations of mood disorder, mood swings, childbirth, spring or summer season, increased libido, thrill seeking, hallucinations or other mood incongruent psychotic features, anger, and racing thoughts. A popular screening instrument for BSD is the Mood Disorder Questionnaire (MDQ).11 Most patients can complete this simple test within 5 minutes. The test is available online at http://www.psycheducation.org/PCP/handouts/mdq.doc.

Mood stabilizers (such as lithium and anticonvulsants) and atypical antipsychotics are the proper treatment for bipolar depression. The atypical agents, including olanzapine, risperidone, and quetiapine, are efficacious in treating the manic and the depressive phases of bipolar disorder.12 At first blush, the idea that an antipsychotic would treat depression is counterintuitive. However, atypical antipsychotics, by definition, have serotonin (5-HT) activity in addition to dopaminergic activity. Specifically, atypical antipsychotics, antidepressants, and electroconvulsive therapy (ECT) treat depression by down-regulating 5-HT(2A) receptors.13 Monotherapy with antidepressants is not recommended in patients with BSD because of the risk of inducing a manic episode.13

ELEVATIONS IN BLOOD PRESSURE WITH VENLAFAXINE
The American Psychiatric Association (APA) Practice Guidelines list venlafaxine as one of several optimal antidepressants.14 Because venlafaxine is not highly protein-bound and lacks significant cytochrome P-450 inhibition, a well-respected cardiology textbook recommends venlafaxine in patients with depression and comorbid cardiovascular conditions.15 The text asserts that venlafaxine has few cardiovascular adverse effects and no effects on ECGs in patients without preexisting cardiovascular disease.15 In fact, venlafaxine is associated with a slightly decreased risk of acute myocardial infarction.16,17

Nevertheless, venlafaxine is associated with elevated blood pressure (BP), which is consistent with its norepinephrine mechanism of action. For a detailed discussion of the relationship between venlafaxine and elevated BP, as well as a discussion of the medical indications for ECGs in patients who are prescribed venlafaxine, please see Venlafaxine and Cardiac Illnesses, an issue of the previous eMedicine Depression and Anxiety Feature Series.18

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With venlafaxine immediate release (IR), BP elevations are dose-dependent and are uncommon at dosages less than 225 mg/d.19 For venlafaxine extended release (XR), the incidence of sustained hypertension (diastolic BP >89 mm Hg or >10 mm Hg above baseline for 3 visits) with venlafaxine is 3% in patients taking less than 101 mg/d, 5% in patients taking 101-200 mg/d, 7% in patients taking more than 200 mg/d, and 13% in patients taking more than 300 mg/d, with 2% of patients taking placebo.20 Elevations in BP are independent of age, gender, baseline BP, renal status, and hepatic status.20 Preexisting mild BP elevations are not a risk factor for elevated BP as an adverse effect of venlafaxine.21

Clinicians should obtain baseline BPs and check BPs regularly in patients taking any form of venlafaxine, particularly those patients taking 225 mg/d or more. Of note, elevated BP occurs most commonly within the first 2 months of venlafaxine treatment.20

SEIZURES
Seizures are an uncommon but possible adverse effect of nearly every antidepressant.23 The antidepressant most associated with seizures is bupropion (Zyban, Wellbutrin). The incidence of seizures with bupropion dosages of 450 mg/d or less ranged from 0.35-0.44%; the cumulative 2-year risk of seizures in patients who received the maximum recommended dosage of 450 mg/d or less was 0.48%.24 The risk of seizure is dose-dependent, particularly with bupropion dosages above the recommended maximum of 450 mg/d.24,25

Well-known risk factors, and, thus, contraindications, to bupropion use include head trauma, seizures, substance abuse, eating disorders, and dosages higher than 450 mg/d. Other risk factors include sleep deprivation and a history of attention-deficit/hyperactivity disorder.26,27 Concomitant use of other medications that lower seizure threshold may also predispose patients to seizures.28 For instance, the literature reported a case of a patient who had a seizure while taking trimipramine and bupropion.29

For SSRIs and mirtazapine, the risk of seizure is generally considered to be low (0.0-0.4%) and not significantly different from the incidence of first seizure in the general population (0.07-0.09%).23 Seizure risk with tricyclic antidepressants at therapeutic doses is 0.4% to 1-2% and is dose-dependent.23,24 Patients without risk factors for seizure had a seizure incidence of approximately 0.6-0.9% when taking imipramine at dosages greater than 200 mg/d. At lower doses, the frequency of seizures dropped to approximately 0.1% or less for imipramine.25 Fortunately, in patients not predisposed to seizures, the potential of seizure caused by antidepressant use is low.23

One study of bupropion overdoses found a 37% incidence of seizures.30 The seizures were dose-dependent and involved dosages significantly higher than the average therapeutic dose. All seizures were brief and self-limiting, and no patients died.30 Another study, which involved 385 patients who overdosed, found that 26% of patients experienced significant clinical effects and 11% had seizures, most of which occurred within 6 hours of the overdose. Associated symptoms included agitation, tachycardia, and hallucinations; if those symptoms persist, seizures are more likely even beyond 6 hours after the overdose.31 A third study evaluated 7,348 cases of bupropion overdose in children and adolescents. Most of these overdoses involved the sustained-release (SR) form of bupropion. Fifteen percent of these patients had seizures.32

A study published in 2002 reported that, after cocaine intoxication and benzodiazepine withdrawal, bupropion was the third leading cause of drug-related, new-onset seizures. Of greater concern is that all bupropion-related seizures in this study occurred in patients on a therapeutic dose of 450 mg/d or less.26 Although rare, patients have died after overdosing on bupropion and having seizures.33 Seizures may also occur in infants who received bupropion through breast milk.34,35

As a part of a good history, clinicians should ask patients if they have ever had a seizure, eating disorder, substance abuse, or head trauma. Individuals who have any of these histories are not good candidates for bupropion. Despite the possibility of seizures, Fava et al from Harvard assert that “bupropion has played and will continue to play an important role as a treatment for major depressive disorder in adults, as well as for other related disorders.”36

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Experimental Medication Ketamine Relieves Depression In Just Hours: Points To Targets For New Medications

July 26, 2007

Ketamine blocks a receptor called NMDA on brain cells, an earlier NIMH study in humans had shown, but the new study in mice shows that this is an intermediate step. It turns out that blocking NMDA increases the activity of another receptor, AMPA, and that this boost in AMPA is crucial for ketamine’s rapid antidepressant actions. The study was reported online in Biological Psychiatry on July 23, by NIMH researchers Husseini K. Manji, MD, Guang Chen, MD, PhD, Carlos Zarate, MD, and colleagues.

“Our research is showing us how to develop medications that get at the biological roots of depression. This new finding is a major step toward learning how to improve treatment for the millions of Americans with this debilitating disorder; toward eliminating the weeks of suffering and uncertainty they have to endure while they wait for their medications to work,” said NIH Director Elias Zerhouni, M.D.

Almost 15 million American adults have a depressive disorder. During the long wait to begin feeling the effects of conventional medications, patients may worsen, raising the risk of suicide for some. Depressive disorders also affect children and adolescents.

By aiming new medications at more direct molecular targets, such as NMDA or AMPA, scientists may be able to bypass some of the steps through which current antidepressants indirectly exert their effects — a roundabout route that accounts for the long time it takes for patients to begin feeling better with the conventional medications.

While ketamine appears to achieve this, it is an unlikely candidate to become a new treatment for depression, because of the side effects it can cause in humans, including hallucinations. It is approved as an anesthetic by the Food and Drug Administration at much higher doses than those given in the study, but its use is limited because it may cause hallucinations during recovery from anesthesia.

Both NMDA and AMPA are receptors for the neurotransmitter glutamate, one of the chemical messengers that enable brain cells to communicate with each other. The glutamate system has been implicated in depression recently, leading to efforts to unravel its molecular machinery in search of abnormalities and of better targets for antidepressant medications.

This focus on the glutamate system is a departure from the thinking that led to currently available antidepressants, which are thought to relieve depression through a lengthy trickle-down process of biochemical reactions that affect the circuitry underlying depression.

Discount Pharmacy - Buy Pharmacy at discount prices including free shipping.Discount Pharmacy provides confortable and easy way to order discount pharmacy online.The fact that NMDA and AMPA receptors are part of the glutamate system and that targeting them directly led to such rapid, sustained relief of depression-like behaviors in this study — and that a single dose of ketamine did the same in humans in the earlier study — suggests that they are probably the key targets for antidepressant medications.

“In any other illness of depression’s magnitude, patients aren’t expected to just accept that their treatments won’t start helping them for weeks or months. The value of our research on compounds like ketamine is that it tells us where to look for more precise targets for new kinds of medications that can close the gap,” said NIMH Director Thomas R. Insel, MD. “We’re making tremendous progress.”

To conduct the new study, researchers induced depression-like behaviors in mice; for example, the mice gave up after being forced to engage in hopeless tasks, such as prolonged swimming. A dose of ketamine reversed the depression-like behaviors for at least two weeks.

When the researchers gave the mice a substance that blocks the AMPA receptor beforehand, ketamine was not able to reverse the depression-like behaviors. The boost in AMPA thus appears to be a necessary ingredient for ketamine’s antidepressant effects.

In a related experiment, the scientists used two different compounds instead of ketamine to try to block just one part of the NMDA receptor, an even more precise target. These other compounds also reduced depressive behaviors, suggesting that it may be feasible to develop other fast-acting antidepressants without ketamine’s side effects.

“Today’s antidepressant medications eventually end up doing the same thing, but they go about it the long way around, with a lot of biochemical steps that take time. Now we’ve shown what the key targets are and that we can get at them rapidly,” said Zarate. “Ketamine probably can’t become the medication of choice, but this research is leading to some very real possibilities for a whole new generation of antidepressant medications.”

Reference: Maeng S, Zarate Jr. CA, Du J, Schloesser R, Joseph M, Chen G, Manji HK. Cellular mechanisms underlying the antidepressant effects of ketamine: role of AMPA receptors. Biological Psychiatry, online ahead of print, July 23, 2007.

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Dr. Gott: Does Zoloft live up to the hype?

July 22, 2007

I read an article a few months ago in which you responded to a reader’s question on depression. You told the reader that Zoloft was a good medicine. A good medicine? It’s proven that this drug causes more suicides in children and teens than any other antidepressant. It’s even tied in with a few adult suicides.

The reader asked if there were any natural things she could use for depression, and you said there wasn’t. Did you ever hear of fish oil? I use it, and it works just as well, if not better, than the prescription drugs you doctors write for us.

Dear Reader: I don’t agree with your statements. Although Zoloft can increase the risk of suicide in a small number of patients, its benefits outweigh its risks.

Omega fish oil, which is an alternative medication to lower cholesterol levels, does not enjoy the reputation of being an antidepressant as well. The jury is still out on the effectiveness of St. John’s Wort, an alternative nonprescription therapy.

Dear Dr. Gott: For a year or two, I had a wart-like thing growing along the side of my thumbnail. It extended from the top of my nail to the cuticle. I would often catch and tear it, and it would bleed. When I pared it off, it would grow back bigger.

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I recently scrubbed the tile grout in my kitchen with a bleach solution. I usually wear rubber gloves, but this time I didn’t. Two weeks later, I noticed the warts were gone. I am delighted! I wonder if the bleach solution killed the wart virus.

Also, when I recently saw the advertisement for Lamisil ointment for rough heels, I decided to apply Vicks VapoRub to mine and noticed a difference in just two days. I had previously tried Bag Balm, going to bed with socks on, other ointments, pumice stones and appliances that rub the skin off, all to no avail.

Dear Reader: The bleach probably killed the wart viruses. Continue the treatment as needed.

I recently heard of a woman with an identical problem who used duct tape, and her warts disappeared. Imaginative, alternative treatments continue to astound me. I cannot always endorse them, but I can certainly pass them on for readers to consider.

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