Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00457106 |
| Other study ID # |
IRB#: 082-02 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 3, 2007 |
| Last updated |
November 30, 2010 |
| Start date |
June 2002 |
| Est. completion date |
June 2003 |
Study information
| Verified date |
November 2010 |
| Source |
Beth Israel Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
This study compares the efficacy of risperidone to that of paroxetine in the treatment of
panic attacks in patients with Panic Disorder and with Major Depressive Disorder with Panic
attacks and compares the side effect profile of risperidone vs. paroxetine in treatment of
panic attacks and compares response rates of risperidone vs. paroxetine in treatment of
panic attacks.
Description:
Rationale
Risperidone is an atypical antipsychotic drug that acts as an antagonist at 5-HT2A/2C and D2
receptors (Chouignard et al, 1993; Marder & Meibach, 1994). In its serotonergic activity,
risperidone resembles both the atypical antidepressant and 5HT2-antagonist nefazodone
(Bakish et al, 1993) and a 5HT2-antagonist ritanserine (Lima & Moncrieff, 2000; Preskorn
1995). Nefazodone treats anxiety symptoms and induces less agitation than other reuptake
blockers (Fawcett et al, 1995) while ritanserin shows effectiveness in treatment of
dysthymia in clinical trials. Moreover, risperidone increases release of dopamine and
norepinephrine in the prefrontal cortex (Zhang et al, 2000), an activity that in other
pharmacological agents is associated with their antidepressant, anxiolytic, and antipanic
properties (Thase, 2002).
Therefore, risperidone has a potential to be effective for treatment of either Generalized
Anxiety Disorder, or Panic Disorder, or Major Depressive Disorder with Panic Attacks
(DSM-IV, 1994) as a single agent. Moreover, due to its D2 and 5-HT2A/2C antagonism and
proven antipsychotic efficacy, the drug could be uniquely effective for severe panic attacks
with psychotic features or para-psychotic features (Galynker et al, 1996). Consistent with
this supposition, Marder et al (1997) reported that in patients with schizophrenia,
risperidone produced significantly greater improvements than haloperidol in PANSS scores
measuring anxiety and depression.
Our clinical experience with over 50 patients with panic attacks showed that low dose
risperidone, similar to lorazepam, reduced or eliminated anxiety and panic, often after the
first dose. Risperidone was most effective for patients experiencing obsessive, intrusive,
anxiety-inducing thoughts. In contrast to lorazepam, risperidone treatment did not result in
building of tolerance to the drug or disinhibition. We did not observe extrapyramidal side
effects in patients treated with risperidone for panic attacks. Thus, our preliminary
clinical data indicate that due to its efficacy, quick onset of action, absence of addictive
potential, and lack of side effects, risperidone could be superior to both benzodiazepines
and SSRIs for treatment of panic attacks, particularly for severe panic attacks. Moreover,
risperidone has a potential to be the first line drug for treatment of these symptoms.
Consequently, at present, a clinical study of risperidone for treatment of panic attacks is
indicated and is of great potential value. We propose an exploratory, open-label,
single-blind trial of risperidone vs. paroxetine for treatment of panic attacks.
Hypothesis/Objectives
Objective One: To compare the efficacy of risperidone to that of paroxetine in treatment of
panic attacks in patients with Panic Disorder and with Major Depressive Disorder with Panic
attacks.
- Hypothesis One: Risperidone and will be more efficacious in treatment of panic symptoms in
both patient groups.
Objective Two: To compare the side effect profile of risperidone vs. paroxetine in treatment
of panic attacks.
- Hypothesis Two: Risperidone, compared to paroxetine, will cause less sexual side
effects, anxiety, and restlessness. There will be no difference in extrapyramidal side
effects between the paroxetine and the risperidone groups.
Objective Three: To compare response rates of risperidone vs. paroxetine in treatment of
panic attacks.
- Hypothesis Three: Patients with panic attacks will respond significantly faster to
risperidone than to paroxetine.
Objective Four: To examine demographic and clinical predictors of robust response to
risperidone treatment using appropriate statistical analyses of individual scales items and
treatment response rates.
- Hypothesis Four: The subgroup of participants who have high scores on items reflecting
somatic anxiety, and ruminative-intrusive thinking, and those with nocturnal panic
attacks will show better response to risperidone therapy than patients with low scores
on those items.
If study hypotheses are confirmed, future research could include a randomized, double-blind,
fixed-dose study of risperidone as the sole agent for treatment of panic disorder and Phase
IV trials aimed at determining the effectiveness of 0.125 mg and 0.0675 mg doses of
risperidone for the treatment of anxiety and panic attacks.
Study Population
The patient population will consist of psychiatric outpatients who meet criteria for the
DSM-IV diagnosis of Major Depressive Disorder with Panic Attacks or Panic Disorder. The
subjects will be primarily recruited from the Psychiatric Outpatient Services for Adults
clinic (POSA) located at Beth Israel Medical center that provides care to approximately 900
patients per year. At present, the patient ethnic and racial mix at POSA is 50% Hispanic,
15% African American, 32.5% Caucasian and 2.5% Asian. The gender distribution is
approximately 33% male and 67 % female. The outpatient payer mix is 20 % Medicare, 74 %
Medicaid and 6% combined. Of those patients, approximately 40% (360) manifest panic attacks.
In addition, patients will be recruited from the Emergency Department and from inpatient
psychiatric units at Beth Israel Medical Center and from newspaper advertisements. Based on
our previous experience with recruitment for research studies, we expect that 10-12% of
patients (36-42) who meet diagnostic criteria will also meet inclusion and exclusion
criteria, will sign informed consent and will participate in the study. We expect to recruit
40 patients per year and to complete the study in 4 years.
Inclusion Criteria
1. Males and females, ages 18-55.
2. Ability to sign an informed consent
3. Diagnosis of Panic Disorder, or MDD with Panic attacks, single episode, recurrent, or
chronic
4. HAM-A score >17
Exclusion Criteria
1. Alcohol or substance abuse within the last 6 months
2. Current diagnosis of Obsessive-Compulsive Disorder
3. Current diagnosis of Schizophrenia, Schizoaffective Disorder, or Bipolar Mood Disorder
4. Use of antipsychotic medications over the two months preceding enrollment in the study
5. Changes in antidepressant or mood stabilizer dosing over the two months preceding
enrollment in the study
6. Previous adverse reaction to risperidone or paroxetine.
Study Design and Drug Regimens
The study will be an 8-week parallel comparison (with a blinded rater) of risperidone and
paroxetine for treatment of three groups of patients with panic attacks. Each group will
consist of 30 subjects.
After signing an informed consent, the subjects will be randomly assigned in an open manner
to treatment with risperidone or paroxetine alone.
Arm 1: Treatment with risperidone will be flexible-dose and will be initiated at 0.25 mg po
qhs. For the subjects who did not achieve a remission of panic symptoms, the dose will be
increased to 0.5 mg po qhs on day 3. For subjects who experienced morning sedation, the dose
will be decreased to 0.125-mg po qhs on day 3.
Arm 2: Treatment with paroxetine will be flexible-dose and will be initiated at 10-mg po
qhs. For subjects who experienced morning sedation, the dose will be decreased to 5-mg po
qhs on day 3. For the subjects who did not achieve a remission of panic symptoms, the dose
will be increased to 20-mg po qhs. For the subjects who did not achieve a remission of panic
symptoms, the dose will be increased to 40-mg po qhs as needed.
Arm 3: Treatment with paroxetine on a fixed dose schedule will be initiated at 10 mg po qhs
on day 1. On day 3 it will be increased to 20 mg po qhs. On day 7 it will be increased to 30
mg po qhs. Most patients respond to an average therapeutic dose of 30 mg of paroxetine. Many
patients in Arm 2, since it was flexible-dose, never achieved a therapeutic dosage, which
could potentially create a bias in the comparison. The third arm was added to ensure that a
subgroup of study participants would receive an optimum therapeutic dose of paroxetine, to
allow for an unbiased comparison between the two study drugs.
Patients randomized on any of the above arms, and not responding or having side effects will
be taken off the study and referred for regular psychiatric treatment.
Subjects receiving fixed dose antidepressants or mood stabilizers prior to their enrollment
in the study will be continued on these medications throughout the study. No dose adjustment
of antidepressants or mood stabilizers will be allowed. At the end of study, participants
can choose to continue their study medications under the care of one of study physicians or
one of the other psychiatrists at POSA. Those wishing to stop study medications at the end
of the study will be able to do so under the supervision of one of the study physicians.
Paroxetine will be tapered over a two-week period to avoid SSRI withdrawal. Risperidone will
be stopped abruptly since no withdrawal symptoms have been reported in the literature.
Assessments to evaluate mood and severity of panic attacks will be performed by a rater
blinded to medication status on a weekly basis.
All study participants' will receive psychiatric treatment, free of charge, for at least one
month following the end of the study. At the end of that period, participants will be
assisted in finding further psychiatric care. Subjects will receive $10 (paid in cash) as
reimbursement for travel expenses for each assessment that they attend. Subjects will have
to sign a receipt of reimbursement in order to receive the cash.
Data Analysis
Pearson Product Moment correlation coefficients (r) will be calculated for each of the
treatment outcome variable groups. This will enable determination of the degree of
association between treatment and outcome. More importantly, (r) can be interpreted with the
Binomial Effect Size Display (BESD) (Rosenthal, 1991). The BESD will enable estimation of a
clinically meaningful improvement rate and the number of people that would improve as a
result of treatment.
Power Analysis and Precision Analysis
As stated above, the measure of effect size will be the Pearson Product Moment correlation
coefficient (r). For this study, the effect size of r = .50 was chosen as the smallest
effect size that would be clinically meaningful, and a sample size of 26 was calculated as
necessary to obtain power of 81% and a 95% confidence interval (r = .13 to r = .75) that
would not include zero (Rosenthal, 1991).
