1998 APA Report, Part III

October 1, 1998

Atypical antipsychotic treatment for borderline personality disorder (BPD) and augmentation therapy with olanzapine (Zyprexa) or estrogen replacement therapy (ERT) for patients with mood disorders were among the research questions addressed at the American Psychiatric Association's annual meeting in Toronto. Following are some brief reports of selected presentations.

(This is the third in a series of reports summarizing research presented at the American Psychiatric Association meeting in Toronto. Part I appeared in the August issue, and Part II in the September issue-Ed.)

Atypical antipsychotic treatment for borderline personality disorder (BPD) and augmentation therapy with olanzapine (Zyprexa) or estrogen replacement therapy (ERT) for patients with mood disorders were among the research questions addressed at the American Psychiatric Association's annual meeting in Toronto. Following are some brief reports of selected presentations.

Renal Function in Response to Lithium Administration

Because of the existing reports of patients who are experiencing renal failure while being treated with lithium (Eskalith, Lithobid), there exists guarded concern about the administration of lithium. To gauge the frequency of clinically significant changes in renal function during lithium maintenance and to examine potential risk factors, a chart review was conducted at Massachusetts General Hospital in Boston.

Patients treated with lithium for three or more years were targeted by the investigators. The gathered data allowed the determination of change from baseline creatinine at three-year intervals. They evaluated whether a significant change in creatinine (0.2 mg/dL)² in the first three years was correlated with further increases in creatinine from three to six years.

Of the 79 patients who were treated with lithium for three or more years (17 were treated for nine or more years), 27 had a significant increase in creatinine. A Spearman's rank correlation was used to examine the relationship between significant changes in creatinine in the first three years with changes from three to six years.There was no specific relationship identified (r=-.068; p=0.67). A larger sample population is needed to examine whether significant changes in creatinine by year 3 are correlated with changes at six years to nine years, and nine years to 12 years (Demopulos CM et al., New Research 38).

Repetitive Transcranial Magnetic Stimulation Versus ECT for MDD

Researchers at Chaim Sheba Medical Center in Israel conducted a study to compare the efficacy and the side effects of repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) for patients with major depressive disorder.

Twenty patients were randomized to two groups and treated with either (rTMS or ECT. Severe major depression was diagnosed in all patients as measured by the 21-item Hamilton Depression Rating Scale (HAM-D-21>20). The HAM-D, Brief Psychiatric Rating Scale (BPRS), Pittsburgh Sleep Quality Index (PSQI), Global Assessment Scale (GAS) and Global Depression Rating (GDR) were used for evaluation at baseline and at the end of the second and fourth weeks of treatment. Up to 20 rTMS sessions were administered with a magstim rapid machine to the left prefrontal region of the head, and given at 90% of motor threshold.

During each session, 20 two-second trains at 10 Hz frequency, with a 45-second interval between trains, were administered. ECT was given following the guidelines of the American Psychiatric Association. Seizure threshold was determined at baseline, and consecutive treatment was administered at 2.5 times baseline energy. Electrode placement was unilateral at baseline in all cases. Cases that responded slowly to ECT were switched to bilateral placement from the seventh treatment.

ANOVA (analysis with variance) with repeated measures comparing baseline and week 4 clinical ratings for the HAM-D (f:19.9, p<0.0001), BPRS (f:12.3,p<0.0001), PSQI (f:10.5, p<0.0003), GDR (f:16.9, p<0.0001), and GAS (f:24, p<0.0001) demonstrated significant effect of treatment. However, a group effect was not observed. Therefore, it appears that ECT and rTMS have similar degrees of efficacy in dissolving depressive symptoms (Dannon PN et al., New Research 44).

Fluvoxamine and Enuresis in Children and Adolescents

Antienuretic properties are present in tricyclic antidepressants, but they are not regularly used in children because of their side effect profile. The selective serotonin reuptake inhibitors (SSRIs) have antidepressant properties similar to the tricyclics, but they are safer for use in children.

Investigators at the Tel Aviv Community Mental Health Center in Israel evaluated the efficacy of fluvoxamine (Luvox) and its antienuretic properties in children and adolescents. Nine children, ages 9 to 14, participated in the study. All of the patients had primary enuresis that was resistant to behavioral therapy. They were treated with fluvoxamine, 75 mg/day to 100 mg/day. Four patients received fluvoxamine purely to relieve their enuresis, while the remaining five received it for other primary indications. Enuresis was monitored daily, and mean voiding frequency was compared between three phases: baseline, on treatment and off treatment.Treatment with fluvoxamine had no statistically significant effect on enuresis. However, a decrease in voiding frequency was observed in three children on fluvoxamine treatment. Thus, the researchers concluded that fluvoxamine does not contain significant antienuretic properties. They suggested that the combination of serotonergic with anticholinergic activity is a major factor in the antienuretic activity. When treating children or adolescents with obsessive-compulsive disorder and comorbid enuresis, clomipramine (Anafranil) is a more effective method of pharmacotherapy than fluvoxamine (Toren P et al., New Research 46).

Risperidone for Treatment of Dementia and Risk of Tardive Dyskinesia

A multicenter, double-blind study was conducted in 625 institutionalized dementia patients (73% with Alzheimer's disease, 15% with vascular dementia, 12% with mixed dementia) to evaluate the efficacy and safety of risperidone (Risperdal). Patients were randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day or 2 mg/day of risperidone for 12 weeks.

According to scores on the Behavior Pathology in Alzheimer's Disease Rating Scale and the Cohen-Mansfield Agitation Inventory, significantly greater improvements were seen in psychosis and in the frequency and severity of aggressive behaviors in patients receiving 1 mg/day or 2 mg/day of risperidone than those receiving placebo. The frequency of adverse events, including extrapyramidal symptoms, was similar in patients receiving risperidone at 1 mg/day and placebo.

Two hundred and sixteen of the patients are participating in a one-year, open-label follow-up study. To date (May 1998), they have been exposed to risperidone for a mean ( SD) of 184128 days (69% have been exposed >90 days). No cases of tardive dyskinesia have been reported, and the patients show improvement on five measures of dyskinesia: dyskinetic movements, hyperkinesia, buccolinguomasticatory factor, choreoathetoid movements and clinical global impression of dyskinesia (Brecher MB, New Research 342).

Lesser Susceptibility to Nicotine in Patients with Parkinson's Disease

Substantial loss of nicotinic receptors in patients with Parkinson' disease (PD) has been demonstrated in postmortem studies. This may account for some of the cognitive, motoric and behavioral deficits seen in PD patients.

Epidemiologic studies have suggested that cigarette smoking is a strong negative risk factor for the development of PD. Blockade of central nicotinic receptors has been shown to produce cognition impairment in areas of new learning, short-term memory and psychomotor slowing, with increasing dose sensitivity with age and disease.

Studies of acute stimulation of nicotinic receptors in Alzheimer's disease with nicotine and the novel agonist ABT-418 have shown improvement in several measures of cognitive function. Prior studies of the effects of nicotine in PD have suggested some improvements in clinical symptomatology.

Quantitative dose-ranging studies of both acute and chronic nicotine in PD, to assess cognitive and motor effects in nine nondemented subjects with early to moderate PD, have been done. The subjects were given intravenous nicotine up to 125 µg/kg/min, followed by chronic administration of nicotine by transdermal patch with doses ranging up to 14 mg/day for two weeks. Testing occurred both during drug administration and up to two months after drug cessation for prolonged effects.

Preliminary analysis showed improvements after acute nicotine in stimulation in several areas of cognitive performance, particularly measures such as reaction time, central processing speed and decreased tracking error; improvements in attention and semantic retrieval were not seen. After chronic nicotine stimulation, improvements were seen in several motor measures, suggesting improved extrapyramidal functioning. This appeared to be sustained up to one month after drug discontinuation. Treatment was well tolerated, suggesting that nicotine stimulation may improve both cognitive and motor aspects of PD (Newhouse PA et al., New Research 356).

Genetics and Tardive Dyskinesia

To ascertain a possible genetic component to tardive dyskinesia (TD), the relationship between presence or absence of TD and the dopamine D3 receptor (DRD3) and the serotonin2A (5-HT2A) receptor gene was examined in 91 schizophrenic patients in a long-stay state hospital.

In this case-control design study, quantitative measures of TD were tested with ANOVA. This disclosed a positive association for orofacial movements and the DRD3 gene (p=0.004), and for abnormal movements in the extremities and the 5-HT font size="-2">2A gene (p=0.002). Interaction between the two polymorphisms seems to be of paramount importance on abnormal movements in both areas.

This data suggest that the occurrence of TD is probably highly related to a genetic predisposition whose effects become phenotypically evident with the significant contribution of other variables, especially neuroleptic treatment and aging (MacCiardi F et al., New Research 384).

Estrogen Replacement Therapy and Augmentation of Sertraline

To determine if estrogen replacement therapy (ERT) may augment antidepressant response to sertraline (Zoloft), 34 depressed female outpatients receiving sertraline and ERT were compared with 93 women who were receiving sertraline but not ERT. They were enrolled in either of two 12-week, randomized, double-blind, multicenter trials comparing sertraline (50 mg/day to 150 mg/day) with either fluoxetine (Prozac) in one trial or nortriptyline (Pamelor, Aventyl) in the other.

Based on Clinical Global Impression (CGI) scores, sertraline-treated women on ERT had substantially greater improvement than sertraline-treated women not taking ERT. There was a statistical trend for similar results on CGI mean change and on the proportion of women "remitting" (defined as HAM-D-17 scores =7).

These findings provide further evidence that ERT may augment clinical response to SSRI antidepressant treatment in older depressed women. ERT status of postmenopausal women should be considered during both treatment and the planning of clinical trials (Schneider LS et al., New Research 426).

Relapse in Patients with Obsessive-Compulsive Disorder

To investigate if patients with obsessive-compulsive disorder (OCD) who relapse after drug discontinuation are responsive to drug reinstitution, a six-month, open-label reinstitution study was performed. A total of 81 outpatients who were responders (Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] score decrease >40%) to a prior trial (six months) with clomipramine 150 mg/day, fluoxetine 40 mg/day, fluvoxamine 300 mg/day or paroxetine (Paxil) 40 mg/day and who relapsed within six months of discontinuation, had the same treatment reinstituted (18 were retreated with clomipramine, 22 with fluoxetine, 21 with fluvoxamine and 20 with paroxetine). Each patient was scored on the Y-BOC Scale before entering the study and every two weeks until endpoint. Patients with at least 40% decrease of Y-BOCS score were rated as responders.

At endpoint, the response rate was 83.3% with clomipramine, 81.8% with fluoxetine, 80.9% with fluvoxamine and 80% with paroxetine-response rates considerably lower than the 100% rates of the first treatment with these drugs. Furthermore, Y-BOCS scores for the four groups showed a slower decrease after drug reinstitution than in the first trial.

Thus, relapsed OCD patients retreated with the same drug may respond to the same drug, but not as well or as quickly as the first time (Ravizza L et al., New Research 443).

Risperidone, Gender-Specifics and Prolactin Response

During a six-month, double-blind, controlled, comparative clinical trial of olanzapine and risperidone performed predominantly on patients with schizophrenia, serum prolactin was assessed at baseline, after completion of up to eight weeks acute treatment and after 28 weeks extended treatment.

After both treatment periods, mean prolactin for risperidone-treated males and females was significantly higher than that of olanzapine-treated males and females. Mean prolactin after acute and extended olanzapine treatment was not significantly different from baseline in either gender. Risperidone-treated females had a significantly greater increase in mean change from baseline prolactin than risperidone-treated males after both treatment periods. Mean change from baseline did not differ significantly between olanzapine-treated males and females.

These findings confirm that risperidone may cause an elevation in prolactin in men and women (females?males), whereas olanzapine is not associated with a significant increase in prolactin in either gender (Kinon B et al., New Research 449).

Olanzapine in the Treatment of Mood Disorders

Researchers at George Washington University conducted a study to determine if olanzapine is a safe and effective add-on treatment for outpatients with mood disorders.

All charts of patients meeting DSM-IV criteria for bipolar disorder (n=7, type I, type II, NOS), unipolar major depressive disorder (n=1) or schizoaffective disorder (n=2, 1 bipolar type, 1 depressed type) treated with olanzapine in an outpatient psychiatric practice were reviewed. The CGI Scale for Improvement was used to retrospectively record clinical response.

Among the six males and four females (age 53.5?10.4 years), olanzapine (dose 8.75?8.68 mg/day for 15.1?16.8 weeks) was moderately effective in six (60%). The main indications for treatment were depressive (in six) or manic (in three) symptoms, with equal response in both groups (4/6 and 2/3, respectively). Only one patient possessed psychotic symptoms.

Eight patients reported side effects-most commonly weight gain (n=3); two of the 10 discontinued treatment due to side effects (weight gain, angioedema). Nine patients received mood stabilizers, and seven, antidepressants. Five patients had previously failed to respond to at least one mood stabilizer. Manic psychotic symptoms worsened in two patients-transiently in one case, and more severely in the other.

In conclusion, it appears from this study that olanzapine is an effective add-on treatment for outpatients with mood disorders. While side effects do occur, they usually do not lead to discontinuation (Ghaemi SN et al., New Research 57).

Treating Borderline Personality Disorder with Atypical Antipsychotics

Efficacious treatment of BPD has been achieved with numerous medications, however, acceptability of older medications has been problematic. Researchers from Case Western University conducted a chart review of patients with BPD, most of whom have other comorbid illnesses. The patients were treated with atypical antipsychotics, such as risperidone, olanzapine and clozapine (Clozaril). Twenty-five patient charts were reviewed. The adult patients, ranging in ages from 22 to 54, were 84% female and 84% Caucasian. Numerous medications had been used to treat all patients previously, with only minimal or partial response.

The design of the study included a chart review questionnaire that was systematically applied to the patients' records. The chart review was conducted not only by the clinicians but by other investigators as well. Data collected by the investigators led them to believe that the atypical antipsychotics administered were helpful in reducing a number of the symptoms characteristic of BPD. The CGI scores averaged 6.34 at the end of treatment with atypical antipsychotics. An average increase of 22.6% was observed in the Global Assessment of Functioning (GAF). The symptoms showing the greatest response included mood and affect, paranoia and fearfulness, suicidal thoughts, affective instability, sleep, controls and impulsivity. Additionally, the medications appeared safe and well-tolerated by the patients. These medications offer hope for the future treatment of patients suffering from BPD (Kujawa MJ et al., New Research 84).

Does Corticosteroid Therapy Create Mood Changes?

Corticosteroids are medications that are frequently prescribed for a variety of common illnesses. However, corticosteroid therapy has been known to produce side effects that include mania, depression, mood lability and psychosis. Researchers in the department of psychiatry at the University of Texas, Southwestern, reported preliminary data from an investigation in which they hope to help resolve the ongoing problem of poorly characterized symptoms and risk factors.

The investigation targeted asthma-suffering outpatients (n=23) receiving prednisone (Sterapred) therapy (generally 40 mg/day for one to two weeks). Psychiatric symptoms were characterized using a structured clinical interview, HAM-D, Young Mania Rating Scale (YMRS), BPRS and Internal State Scale (ISS). These data show significant increases in the YMRS (p=0.003) after four to seven days of corticosteroid therapy.

Persons with a history of major depressive disorder showed significantly increased scores on the Well-Being Subscale of the ISS (p=0.04) and a trend towards decreased HAM-D scores (p=0.08) compared with persons without a history of depression.

It has been reported that persons experiencing posttraumatic stress disorder (n=5) sometimes report a worsening of symptoms and depression during prednisone therapy, although this data was not statistically significant. Therefore, these preliminary data suggest that symptoms of hypomania are common with corticosteroids and that psychiatric history may help predict response (Brown ES et al., New Research 99).