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 Primary Psychiatry. 2003;10(11):19,24-28

FDA Approves Memantine for the Treatment of Alzheimer’s Disease

The United States Food and Drug Administration approved memantine (Namenda, Forest) for the treatment of moderate to severe Alzheimer’s disease in October. The recommended starting dosage of memantine is 5 mg QD, with a target dosage of 20 mg/day. Dosages should be titrated in 5 mg increments with a 1-week interval between dosage increases.

The efficacy of memantine, an N-methyl-D-aspartate receptor antagonist, was determined in two double-blind studies involving more than 650 patients with Alzheimer’s disease. By study endpoint, patients improved their scores on cognitive, daily function, and/or global performance assessments. Clinical trials have also suggested that memantine blocks the action of glutamate.

Side effects reported with the use of memantine include dizziness, headache, and constipation, which occurred in ≤7% of patients.

Memantine is expected to be available in pharmacies in early 2004. –CN

Gepirone Extended-Release for Anxious Depression

Gepirone extended-release (ER), a once-daily serotonin 5-HT1A receptor agonist, was shown to be effective and well tolerated in the treatment of patients with major depressive disorder (MDD) and high ratings of anxiety (anxious depression). While previous studies have demonstrated efficacy of gepirone in MDD
overall, this is the first study to focus specifically on anxious depression.

Jonathan E. Alpert, MD, PhD, and Maurizio Fava, MD, at Massachusetts General Hospital in Boston, conducted an 8-week, double-blind, placebo-controlled study evaluating gepirone ER 20–80 mg/day for anxious depression. Patients were selected from a larger group of outpatients who participated in a multi-site study of gepirone ER in patients with MDD. The current study included only the subset of patients who met criteria for both major depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; 17-Item Hamilton Rating Scale for Depression [HAM-D17] score=20) and anxious depression (HAM-D17 anxiety/somatization factor score >6).

Gepirone ER was initiated at a dose of 20 mg/day and increased to 40 mg/day on day 4. The drug was increased to 60 mg/day after day 7 and 80 mg/day after day 14, based on tolerability and clinical response. Dose adjustments thereafter were made within a range of 40–80 mg/day to optimize tolerability and clinical response. Patients were assessed at baseline, and at days 7, 14, 21, 28, 42, and 56.

Gepirone ER produced an early, sustained response to anxiety and was effective in treating the psychic and somatic symptoms of anxiety that often accompany MDD. Beginning on day 14, gepirone ER-treated patients (n=58) showed significantly (P<.05) greater reductions in HAM-D17 total score and in the anxious/somatization subscore compared to the placebo group. Reduction in the mean psychic anxiety scores on the HAM-D17 was seen at each assessment visit for the gepirone ER group.

“Sedation, weight gain, and sexual dysfunction, which are common antidepressant side effects, did not emerge as side effects associated with gepirone,” Dr. Alpert noted. “Gepirone’s side-effect profile may be particularly attractive for individuals with such previous problems on standard, first-line antidepressants.”

Adverse events reported in >10% of gepirone ER-treated patients included nausea, dizziness, diarrhea, headache, insomnia, and nervousness; only nausea and dizziness were statistically significant from placebo.

“Primary care physicians and psychiatrists treat many outpatients with mixed anxiety and depressive symptoms, whether or not they meet criteria for MDD,” Dr. Alpert said. “This study suggests that gepirone may be a novel antidepressant agent with good antianxiety as well as antidepressant effects.”

Alpert and Fava noted that the study supports the hypothesis that 5-HT1A agonist activity is associated with antidepressant effects and that agents that stimulate the 5-HT1A receptor may someday play a role in targeting the large subpopulation of depressed individuals with prominent anxiety, particularly those who have not responded well to the selective serotonin reuptake inhibitors.

Funding for this research was provided by Organon Pharmaceuticals. –DH

(Poster 1.031, ECNP 2003)

GRID Scoring Developed to Enhance Hamilton Rating Scale for Depression

The Hamilton Rating Scale for Depression (HAM-D) is the most widely used and the most trusted method of assessing a patient’s depression and treatment efficacy. The GRID-HAM-D, a new standardized system using GRID
scoring and standard conventions, was developed by academic, governmental, and pharmaceutical industry researchers. Amar Kalali, MD, from the University of California, Irvine, and colleagues, are currently studying the efficacy and consistency of the GRID-HAM-D.

“The HAM-D is known to have many limitations, which are addressed by the GRID,” Dr. Kalali said. “There are many versions of the HAM-D and physicians do not mention which version they used when their papers are published. Research sites are then expected to apply these inconsistent scoring conventions to different patients. Raters are also inconsistent in their interpretation of what the severity level should be.”

Kalali and colleagues studied 45 patients between 18 and 70 years of age who were diagnosed with major depressive disorder (MDD). Patients studied did not have medical conditions that would preclude them from entering a long-term study. Each patient was screened at baseline and assessed weekly for the first month, bi-weekly for the second month, and monthly thereafter for a maximum of 24 months. Patients were assessed at baseline and at week 4 using the GRID-HAM-D. The Structured Interview Guide for the HAM-D (SIGH-D) was used during interim visits and after the visit at week 4. Baseline HAM-D17 scores were 23.2±5.

“The GRID process got companies to agree to one unified scoring convention which clarified what each anchor should represent clinically,” Dr. Kalali said. “The GRID format divided severity into dimensions of intensity and frequency, something good raters should do but the GRID makes all raters think about.”

Kalali and colleagues believe that the GRID-HAM-D is a reliable method of assessing a patient’s depression because of its consistent use by the raters in this study. The researchers noted that the data presented was collected in November 2002 and the study is still ongoing.

“We are working on a much larger international project to develop a whole new scale for the assessment of depression that addresses the limitations of the HAM-D including aspects of depression not currently captured by the HAM-D,” Dr. Kalali said. –CN

(Poster 1.314, ECNP 2003)

Diagnosis of Depression in the Primary Care Setting

When it comes to diagnosing depression, primary care physicians (PCPs) and their patients show high discrepancies in recognizing symptoms, according to researchers at the University of Liege, in Belgium.

In a prospective, multicenter trial, Koen Demyttenaere, MD, and colleagues, evaluated the degree of agreement between the PCP and the patient in diagnosing major depressive disorder (MDD). All of the patients (N=1,072) had a clinical diagnosis of MDD. The treating PCP evaluated Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for MDD for each patient. Patients independently completed the Patient Health Questionnaire (PHQ)—a self-report version of the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire. The PHQ contains items identical to those symptoms used in the DSM-IV.

According to the PCPs, 90% (n=969) of the patients had MDD, while in comparison only 68% (n=668) of patients diagnosed themselves as having MDD. A significant difference in self-diagnosis was noted based on gender: diagnosis of MDD was made by 65% of men compared to 71% of women. Overall PCP?and patient agreement between presence or absence of specific MDD?symptoms was particularly low, ranging from 44% to 97% (Figure). Highest agreement scores were obtained for symptoms of depressed mood, loss of interest, and fatigue, while lowest agreement was found for weight/appetite, agitation, concentration, and suicide/suicidal thoughts. Clinical diagnosis made by the PCP was generally confirmed by the DSM-IV criteria but less by the PHQ.

Presence of comorbid disorders seemed to enhance the agreement of MDD diagnosis made by the PCP and the patient. Comorbidity was assessed with PHQ modules for somatoform disease, panic, anxiety, and alcohol abuse. Forty-two percent (n=385) of patients had a somatoform disorder with women at significantly higher risk (P=.005) than men (odds ratio=1.5). In addition, 29% had panic disorder, with anxiety complaints decreasing with age (P=.015). Finally, 16% were shown to have abused alcohol, with young men living alone have the highest risk of developing alcoholic disease.

Demyttenaere and colleagues noted that, with suicide in particular, the low agreement confirms that it is often difficult for a PCP to evaluate possible suicidal thoughts and intentions of a patient. On the other hand, PCP and patient discrepancy in the weight item may indicate that weight is a factor that is not considered when evaluating depressive disorder. Demyttenaere and colleagues suggest that the results emphasize a need for the use of the PHQ in assessment of depression diagnosis and symptoms severity. They also suggest that combined assessment made by both the PCP and the patient will likely increase the accuracy of depression diagnosis. –DH

(Poster 1.173, ECNP 2003)

Escitalopram Improves Symptoms of Generalized Anxiety Disorder

Generalized anxiety disorder (GAD)
presents with at least three of the following feelings: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and impairing sleep cycle. Recent research has found escitalopram to be an effective long-term treatment option for GAD because it reduces a patients symptoms of anxiety and enhances their overall quality of life.

Jonathan R. T. Davidson, MD, from Duke University Medical School in Durham, North Carolina, and colleagues, studied 526 patients with a mean age of 39.8 years who had a mean GAD duration of 10.5 years. Approximately 38% of patients were previously treated for GAD.

There were initially three, 8-week, placebo-controlled trials of escitalopram in patients with GAD, defined as a baseline Hamilton Rating Scale for Anxiety (HAM-A) score of approximately 23. The patients who completed these trials were then given the opportunity to take part in a 24-week, open-label, flexible-dose study of escitalopram 10–20 mg/day. The researchers also used the Clinical Global Impression (CGI) scale, and Quality of Life (QOL) scales to assess the efficacy of escitalopram in this study.

Two-hundred and ninety-nine (57%) of the patients completed the study. Approximately 10% dropped out due to adverse events, while others were lost to follow-up, did not adhere to the study’s protocol, or withdrew consent.

At baseline, the mean HAM-A score was 13.1. At endpoint, the mean HAM-A score decreased to 6.9 for all responders (92% of all completers). Eighty-four percent of completers rated their HAM-A tension items scores as 0 (“not present”) or 1 (“mild”) and 86% of completers rated their HAM-A anxiety items scores as 0 (“not present”) or 1 (“mild”). A last observation carried forward analysis was used to determine the response rate at endpoint, which was approximately 76%. At baseline, approximately 50% of patients had a response on the CGI-Improvement. At endpoint, this increase to approximately 90% of patients. A response was defined as a CGI-Improvement score of 2. At baseline, the mean QOL score was 55.9; at endpoint, it increased to 60.9.

Approximately 85% of the patients who completed the study had positive improvements in their GAD symptoms when treated with escitalopram. Davidson and colleagues believe that this finding supports the theory that escitalopram is an effective and well-tolerated form of treatment for GAD.

Funding for this research was provided by Forest Laboratories, Inc. –CN

(Poster 3.315, ECNP 2003)

Pharmacokinetic Differences With Fluoxetine in the Elderly

Plasma concentrations of fluoxetine, norfluoxetine, and the combination appear to be higher in the elderly population, particularly women, making them at an increased risk for drug-drug interactions, according to a recent study.

“Fluoxetine is a widely used antidepressant which has marked effect of the cytochrome P450 2D6 enzyme system and has a high potential for interacting with other drugs,” said the study’s lead researcher, James M. Ferguson, MD, at the University of Utah School of Medicine. “Its first metabolic product, norfluoxetine, has a long half-life in children and adults and there has been some indication that the half-life may be extended in the elderly.”

Although most elderly people are on multiple medications with a high risk for drug interactions, little research has been conducted on the metabolism of medications prescribed to this age group, noted Dr. Ferguson. In addition, earlier work on fluoxetine pharmacokinetics did not include women or very old subjects.

To investigate the pharmacokinetics of fluoxetine in the elderly, Ferguson and colleagues enrolled 25 elderly patients, divided into groups of 65–74 years of age and 75–85 years of age, in a 16-week clinical trial. After a 1-week lead-in, patients received fluoxetine 20 mg for 1 week and fluoxetine 40 mg for the next 5 weeks. The drug was then discontinued for the remaining 8 weeks. Blood was examined for fluoxetine and norfluoxetine weekly from baseline to 8 weeks after drug discontinuation (week 16). 

At week 8, average plasma concentration was 303 ng/mL for fluoxetine, 231 ng/mL for norfluoxetine, and a combined value of 533 ng/mL. Plasma levels were similar in the two age groups. Women had significantly higher levels of norfluoxetine and combined fluoxetine and norfluoxetine levels than men (P=.007). The average elimination half-life for norfluoxetine was 13.7 days and a significant difference in estimated elimination half-life was seen between the two age groups (older>younger) and with gender (female>male).

“Using 5 half lives as the recommended amount of time to wash the drug out of a person’s system before the risk of drug-drug interactions is diminished, a prescribing physician may have to wait as long as 3 months before the risk of interactions with fluoxetine and its metabolite is alleviated,” Dr. Ferguson said.

According to Ferguson and colleagues, these data suggest that care should be taken when prescribing fluoxetine for elderly patients, particularly elderly women. Physicians should also be careful when prescribing medications to elderly patients who have been on fluoxetine as the drug interactions may persist for a long time after discontinuation. –DH

(Poster 1.014, ECNP 2003)

Combination Pharmacotherapy and Psychotherapy for Alcoholism Detoxification

Psychotherapy has proven to be one of the most effective methods of alcohol detoxification, playing a major role in the treatment of alcoholism. However, research has found that alcoholics also suffer from anxiety and depressive symptoms. Pharmacotherapy may be a particularly useful adjunct during the early post-withdrawal phase because it can help reduce concomitant psychiatric symptoms, relieve emotional upset, minimize physical and subjective discomfort, and, hence, increase abstinence from drinking.

A study by John Liappas, MD, PhD, and colleagues from the Athens University Medical School in Greece, reviewed the efficacy of alcohol detoxification using psychotherapy and pharmacotherapy with either mirtazapine or venlafaxine. Liappas and colleagues studied two sets of patients diagnosed with alcoholism using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. The first set consisted of 15 alcoholics (8 males, 7 females) with a mean age of 46.7±8 years. Each patient was treated with psychotherapy and adjunctive venlafaxine 150–220 mg/day. The second set featured 15 alcoholics (8 males, 7 females) with a mean age of 45.7±11.7 years and each patient was treated with mirtazapine 30–60 mg/day. The treatment period for both sets lasted 4–6 weeks.

The researchers chose mirtazapine because it has been shown to possess sedative, anxiolytic, and sleep promoting properties. “These are highly desirable during the initial phase of alcohol detoxification due to high levels of anxiety, agitation, and insomnia which are often present during that phase,” Dr. Liappas said. “Venlafaxine was selected because of its well-established rapid antidepressant and anxiolytic action but more energizing profile than mirtazapine.”

Liappas and colleagues used the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A) to assess the psychopathology of the patients. At baseline, patients in the venlafaxine augmentation group had a HAM-D score of 40.3±5.6 and an HAM-A score of 39.5±5.8. At endpoint, the HAM-D decreased to 6.7±2.3 and the HAM-A decreased to 7.3±3.1 (P=.012). At baseline, patients in the mirtazapine augmentation group had a HAM-A score of 36.4±12.8 and an HAM-D score of 40.2±7.2. At endpoint, the HAM-A score decreased to 3.8±4.0 and the HAM-D decreased to 4.1±3.1 (P=.016).

“We hypothesize that mirtazapine, with its specific action on both the noradrenergic and serotonergic system, has more sedative and sleep-promoting effects than venlafaxine; consequently, a more marked decrease on the HAM-A and HAM-D scores was recorded,” Dr. Liappas said.

Liappas and colleagues found that the anxiety and depressive symptoms suffered by alcoholics subside and reach normal levels when psychotherapy and adjunctive pharmacotherapy are given.

“Our study provides preliminary evidence that the addition of an antidepressant agent to the standard alcohol detoxification treatment might help the detoxification process by minimizing physical and subjective discomfort,” Dr. Liappas said. “Consequently, it may improve patient retention in alcohol detoxification programs and, given the importance of this first phase in the treatment of alcohol abuse-dependence, it may prove to be a facilitatory for the long-term abstinence from alcohol.” –CN

(Poster 5.046, ECNP 2003)

Antidepressant Treatment of Social Anxiety Disorder

A recent study showed venlafaxine extended release (XR) to have efficacy and safety rates comparable to paroxetine in the short-term treatment of social anxiety disorder (SAD).

“This is one of the few head-to-head comparisons of drugs in SAD,” noted study author Michael R. Liebowitz, MD, at Columbia University in New York City. “At the time the study was undertaken, only paroxetine had Food and Drug Administration approval for this condition.”

Liebowitz and colleagues randomly assigned adult outpatients (N=440) with generalized SAD to receive flexible doses of venlafaxine XR (75–225 mg day), paroxetine (20–50 mg/day), or placebo for 12 weeks, followed by an optional taper period. The Liebowitz Social Anxiety Scale (LSAS) was used as the primary efficacy variable. Secondary efficacy assessments included the Clinical Global Impression (CGI)-Improvement scale, CGI-Severity scale, the patient-rated Social Phobia Inventory, and the fear/anxiety and avoidance subscales of the LSAS.

The safety and efficacy analyses included 429 and 413 of the participants,respectively. At week 12, mean daily dose was 201.7 mg for venlafaxine XR and 46.0 mg for paroxetine. At this point, improvement on all primary and secondary efficacy measures was significantly greater with venlafaxine XR (59%) and paroxetine (63%) compared to placebo (36%). Mean LSAS scores decreased from 86.5 to 51.5 for the venlafaxine XR group, 47.3 for the paroxetine group, and 64.3 for the placebo group. Significant improvement on the CGI-S was observed beginning at week 2 for the venlafaxine XR group and at week 3 for the paroxetine group. Side effects were similar for both drugs and included abdominal pain, asthenia, anorexia, constipation, dry mouth, nausea, insomnia, sexual dysfunction, somnolence, and sweating.

“The credibility of this study is enhanced by the fact that it found paroxetine to have the same benefit that was found in former studies sponsored by paroxetine’s manufacturer,” Dr. Liebowitz said. He notes that while paroxetine is “enormously helpful” in approximately 25% of patients and “pretty helpful” for another 30%, venlafaxine may be used as an alternative either first-line or in patients who do not tolerate or respond to paroxetine.

“Venlafaxine, like paroxetine, is very helpful for many patients with the generalized subtype of SAD, even if the patients are very disabled and have been ill for 20 years,” Dr. Liebowitz said. “Dramatically helping such patients become less symptomatic and more functional is a matter of weeks borders on the magical.”

Funding for this research was provided by Wyeth Laboratories. –DH

(Poster 3.064, ECNP 2003)

Atomoxetine Improves Symptoms of Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) currently affects between 3% and 7% of school-aged children, leading to significant impairments in a child’s education. When seeking pharmacotherapy for an ADHD child, a major criteria is improvement in the child’s school work.

Margaret Weiss, PhD, FRCP, of the University of British Columbia in Vancouver, Canada, and colleagues, conducted a double-blind, placebo-controlled, randomized study of 153 children between 8 and 12 years of age to determine the efficacy of atomoxetine in the school setting. All of the children were diagnosed with ADHD and its subtypes, using criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The researchers included children with a symptom severity of 1.0 standard deviation above age and sex norms on the ADHD Rating Scale-IV-Teacher Version (ADHD RS), an 18-item scale covering symptoms of hyperactivity, impulsivity, and inattention, as described in the DSM-IV, and a mean Connors’ Parents Rating Scale ADHD Index score at least 1.5 above the standard deviation for age and sex norms.

Weiss and colleagues excluded children currently taking a psychotropic medication, those with a serious medical illness, those with evidence of a significant intellectual deficit, and children whose primary teacher refused to cooperate. Thirty percent of the patient population had an oppositional defiant disorder (ODD) and 30% had a learning disability. These children were included in the study to analyze the effect of atomoxetine.

Patients were given atomoxetine 0.8 mg/kg/day for the first 3 days which was increased to 1.2 mg/kg/day for the next 2.5 weeks. The dosage was then adjusted between 0.8 mg/kg/day and 1.8 mg/kg/day based on individual patient’s response and tolerability. Each dosage was administered in the morning because previous research has found this time of day to be the best time to administer atomoxetine.

Weiss and colleagues conducted telephone interviews of the patients’ primary teacher as the primary efficacy measure. They asked teachers the extent to which patients were exhibiting these symptoms, which were then rated by the investigators on a 4-point scale.

“This study was designed to look at all aspects of the child’s functioning during the school day as reported by a teacher who has the opportunity to measure the child in classroom situation, while attempting to focus and learn,” Dr. Weiss said. “The result was a clear and valid report of the child’s symptoms, which probably would not have been possible if the teacher had just filled out a form.”

There was 100% response rate from teachers on the ADHD RS, which is significantly more than that achieved (75%) in previous studies that collected forms from teachers by fax or other means. Teachers were asked about the child’s symptoms of ADHD and other disorders, the child’s difficulties and strengths in learning, and how the child behaved during classroom transitions, with other children, and with teachers.

The teachers reported greater reduction in both inattentiveness and hyperactivity/impulsiveness using the ADHD RS. They found that more girls responded to atomoxetine than boys, and that those with prior treatment with a stimulant had a slightly smaller mean change in ADHD RS scores compared to children that were stimulant naive. Patients with an ODD had a smaller response rate than those without an ODD, while patients with a learning disability had a slightly higher response rate than those without a learning disability.

The most common adverse events in this study were decreased appetite, somnolence, vomiting, and irritability.

Weiss and colleagues believe that atomoxetine is a safe and effective method of treating children with ADHD during the school day as the study showed little to no weight gain in the children and there were no significant changes in QTc intervals.

“We have demonstrated that treatment with atomoxetine significantly improves ADHD symptoms at school, and the effect is robust,” Dr. Weiss said. “Future research is needed to determine how treatment helps the child from a child-centered point of view; studies should also look beyond the issue of efficacy for the treatment of ADHD.”

Funding for this research was provided by Lilly Research Laboratories. –CN

(Poster 6.072, ECNP 2003)

Implications of Panic Disorder During Pregnancy and Postpartum

Manifestations of panic disorder appear to be fewer during pregnancy and more frequent in the postpartum period, according to a recent study conducted by researchers at the University of Göttingen in Germany. Small studies on the influence of pregnancy on the course of panic disorder have been inconsistent, some finding that pregnancy offered a protective power over panic disorder while others observing no change or even worse panic symptoms during pregnancy.

Borwin Bandelow, MD, PhD, and colleagues, sought to investigate the impact of pregnancy and the postpartum period on panic disorder in a large sample. Female participants were selected from clinic admission lists, of which 128 participated and were interviewed in person or by telephone. A Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition?was performed to confirm history or present episode of panic disorder and to exclude other relevant psychiatric disorders.

Of the women, 35 had never been pregnant and 93 had been pregnant at least once in their life. There was a total of 195 pregnancies; miscarriages or abortions occurred in 28 patients.

All women completed a questionnaire about panic symptoms. Women with pregnancies were asked an additional 16 questions about panic manifestations during pregnancy and the postpartum period. They were asked to describe the first appearance of panic symptoms and rate exacerbation of pre-existing panic disorder, on a 4-point scale from 1=mild to 4=very severe. Panic manifestation was defined as a first appearance of panic symptoms or an exacerbation of at least moderate severity. The panic manifestation quotient (PMQ) was defined as the panic manifestation period (time with panic symptoms) divided by the observation period (pregnancy=266 days; postpartum=180 days post birth; nonpregnancy period; and nonpostpartum period). Psychosocial stress situations during pregnancy was also rated on a 4-point scale (0=no stress to 4=very severe stress).

Results showed that in women who had been pregnant, panic manifestations were significantly lower during pregnancy than during the nonpregnancy period (Figure). Nine percent of women reported improvement in panic during pregnancy, 84% reported no change, and 7% reported an increase in panic symptoms. The postpartum period was associated with a modest, but significant increase in panic manifestations (PMQ=.19) compared to the nonpregnancy period, and a substantial increase compared to the pregnancy period. Among these women, 3% reported improvement in panic postpartum, 79% reported no change, and 18% reported an increase in panic symptoms.

Approximately 11% reported that they experienced their first manifestation of panic disorder during the postpartum period of one of their pregnancies. This percentage is a 132-fold increase compared with the non-postpartum period. Five women reported onset of the first panic symptoms 1–5 after childbirth.

For statistical purposes, postpartum depression was only calculated for the first pregnancy. Among women who had a child, 37% reported postpartum depression and 20% had postpartum panic manifestations. Both disorders occurred in 12%.

Psychosocial stress was reported in 54% of the women with pregnancies (n=106). Reasons for stress included problems with partnership (25%), family (21%), health (21%), financial or occupational problems (20%), psychological problems (8%), and unwanted pregnancy (5%). In women who reported stress, the risk of developing panic manifestations was increased 1.7-fold for the first pregnancy and 1.5 fold for the second.

Women who never had been pregnant had significantly higher PMQs than age-matched controls who had been pregnant.

Bandelow and colleagues note that their data, based on the largest sample investigated on this subject matter, suggests that pregnancy protects against panic manifestations, while the postpartum period increases the risk for onset or exacerbation of panic disorder. They speculate that hormonal changes may explain the phenomenon as change in panic symptoms pre and postpartum is rapid, coinciding with a sudden drop of hormones after delivery. This is further supported by the fact that normal deliveries produced the same high risk of panic manifestations as miscarriages.

Bandelow and colleagues note that treatment with tricyclic antidepressants and selective serotonin reuptake inhibitors seems to be compatible with breast feeding, although this view should be considered as preliminary due to the lack of data. Breast feeding should probably be discontinued in cases where high-dose long-term administration of anxiolytic benzodiazepines is necessary.

“As medications may be problematic with regard to breastfeeding, cognitive-behavior therapy could be an alternative,”?Dr. Bandelow said. –DH

(Poster 3.308, ECNP 2003)

Effects of Hypnotics on Daily Activities

Poor sleep quality often results in decreased alertness and drowsiness the following day. Benzodiazepine hypnotics can aggravate these effects, resulting in impaired performance during daily activities. A recent study evaluating effects of hypnotics on driving ability found that zaleplon, a new nonbenzodiazepine hypnotic with very selective effects on the
g-aminobutyric acid subreceptors and a short half-life, may provide a safe alternative for patients concerned about impaired performance.

Edmund R. Volkerts, PhD, and colleagues at the Utrecht University in The Netherlands, reviewed the literature consisting of four placebo-controlled, double-blind, on-the-road driving studies to examine the effect of both zolpidem and zaleplon on driving ability. Subjects were instructed to drive in a steady lateral position in the right traffic lane at a constant speed of 95 km/hour. A camera mounted on the roof of the car, continuously recorded the lateral position of the car. Primary parameters of vehicle control were the standard deviations of the lateral position (SDLP) and speed (SDS).

Neither zolpidem nor zaleplon significantly affected driving performance the morning after bedtime administration. However, when administered in the middle of the night, 4 hours prior to awakening, zolpidem significantly impaired driving ability. The impairment produced SDLP increments 4-fold (10 mg dose) and 11-fold (20 mg dose) that of those observed after a blood alcohol concentration of .05%. A significant increase in speed variability was observed as well. In contrast, zaleplon did not affect driving ability 4 hours after administration.

“In contrast to other hypnotics, zaleplon appears to be a safe hypnotic for both genders, with no hangover effects when driving a car the next day even when administered 4 hours before awakening,” Dr. Volkerts said.

Dr. Volkerts notes that that this safety advantage of zaleplon must be taken into account when prescribing a hypnotic drug to outpatients, since most of them are likely to drive. Physicians should instruct patients taking zolpidem that when taken during the night, it is unsafe to drive a car the next day, he said. Regarding zopiclone, Dr. Volkerts points out that patients should be advised not to drive, as studies have shown significant impairment 10–11 hours following bedtime administration of the drug. –DH

(Poster 6.093, ECNP 2003)

Pregabalin Improves Anxiety and Comorbid Depressive Symptoms

The benzodiazepine pregabalin showed significant efficacy in the treatment of generalized anxiety disorder (GAD) regardless of comorbid depressive symptoms, according to a multicentered team of researchers. While benzodiazepines have shown exceptional results in efficacy and speed of anxiety improvement, many show less efficacy in the presence of depressive symptoms.

Mark H. Pollack, MD, of Massachusetts General Hospital, and colleagues, evaluated the influence of subsyndromic depression on the efficacy of pregabalin in GAD. The researchers combined data from five double-blind, placebo-controlled GAD trials of pregabalin. They analyzed doses of 200 mg (n=78), 300 mg (n=91), 400–450 mg (n=364), and 600 mg (n=414). Patients were divided into two subgroups:?low baseline depression (Hamilton Rating Scale for Depression [HAM-D] score <15) and high baseline depression (HAM-D score 15).

Significant improvement on the Hamilton Rating Scale for Anxiety was achieved across all pregabalin doses for both the low depression and high depression subgroups compared to placebo. Significant reductions on the HAM-D score were observed with pregabalin 300 mg/day and venlafaxine 75 mg/day. The efficacy persisted regardless of the presence of moderately severe comorbid depressive symptomatology.

“Pregabalin is emerging as an effective anxiolytic and looks to be both effective in and reduce the mild to moderate levels of depression that frequently accompany GAD,” Dr. Pollack said. “Additional work is needed to examine the efficacy of pregabalin in the presence of syndromic levels of depression.” –DH

Funding for this research was provided by Pfizer Incorporated. PP

(Poster 3.056, ECNP 2003)

Psychiatric Dispatches is compiled and written by Deborah Hughes and Christopher Naccasri.