Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00206765 |
| Other study ID # |
082-02 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
September 13, 2005 |
| Last updated |
October 19, 2012 |
| Start date |
January 2003 |
| Est. completion date |
July 2005 |
Study information
| Verified date |
October 2012 |
| Source |
Beth Israel Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Food and Drug Administration |
| Study type |
Interventional
|
Clinical Trial Summary
We are comparing the efficacy of Risperidone versus Paroxetine in the treatment of panic
symptoms. The study hypothesis is that Risperidone will be a superior medicine for treating
panic.
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 are therefore proposing an exploratory open
label single-blind trial of risperidone in 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. Some patients will improve within 24 hrs.
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 that to paroxetine.
Objective Four. To examine demographic and clinical predictors of robust response to
risperidone treatment using appropriate statistical analysis of individual scales items and
treatment response rates.
Hypothesis Four: The subgroup patients with panic attacks who will 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 to determine the effectiveness of 0.125 mg and 0.0675 mg dose of risperidone
for 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 recruited from the Center for Treatment of Affective Disorders and from the
Anxiety and Trauma Center in the Department of Psychiatry at the Beth Israel Medical center
that provide care to 900 patients. At present, the patient ethnic and racial mix 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.
Based on our previous experience with recruitment for research studies, we expect that
10-12% of patients (36-42) meeting diagnostic criteria will also meet the inclusion and
exclusion criteria, will sign the inform consent and will participate in the study. We
expect to recruit 40 patients per year and to complete the study in 3 years.
Inclusion Criteria
1. Males and females, ages 21-55.
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 the 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..
This will ensure that a subgroup of subjects will receive optimum therapeutic dose of
Paroxetine and also aid to titrate Paroxetine equivalent dose of Risperidone.
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.
The 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 Psychiatric outpatients service for adults
Beth Israel Medical Center 16 Street at First Avenue, 2 Bernstein. Those wishing to stop the
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 making risperidone taper unnecessary.
Assessments to evaluate mood improvement will be performed by a rater blinded to medication
status on a daily basis for the first three days and every other day for the first two
weeks. The assessments (please see Appendix 1 for the assessment battery) will continue
weekly for the rest of the study.
All study participants' will provided with psychiatric treatment, free of charge, at our
clinic, for one month following the end of the study. At the end of one-month period, we
will assist you in finding further psychiatric care. Travel expenses will be reimbursed for
the subjects participating in the study.
Data Analysis
We will calculate Pearson Product Moment correlation coefficients (r) for each of the
treatment outcome variable groups. This will enable us to determine the degree of
association between treatment and outcome. More importantly, we can interpret (r) with the
Binomial Effect Size Display (BESD) (Rosenthal, 1991). The BESD will enable us to estimate a
clinically meaningful improvement rate and to estimate the number of people that would
improve as a result of treatment.
Power Analysis and Precision Analysis
As stated above, our measure of effect size will be the Pearson Product Moment correlation
coefficient (r). For this study we chose an effect size of r = .50 as the smallest effect
size that would be clinically meaningful, and then calculated that we would need a sample
size of 26, to obtain power of 81%, and a 95.0% confidence interval (r = .13 to r = .75)
that would not include zero. (Rosenthal, 1991).
