The purpose of this study is to examine the safety and effectiveness of the drug combination
paroxetine and clonazepam in treating people with panic disorder (PD) and major depression.
The main goal in treating people with PD is to rapidly reduce symptom severity and improve
functioning. While numerous drug therapies have been used to treat PD, these treatments are
limited by variable response rates and suboptimal side effect profiles. Evidence suggests
that clonazepam given with a selective serotonin reuptake inhibitor (SSRI) can facilitate a
rapid reduction in PD symptoms. However, it is unclear whether comorbid depression
influences treatment response to the clonazepam and SSRI regimen. This study will examine
whether combined treatment with clonazepam and the SSRI paroxetine will accelerate clinical
response in participants with PD and comorbid depression. This study will also examine
whether the benefits of treatment will be sustained until the end of the study despite
tapering of clonazepam at the midpoint of the study.
Participants in this study will be screened with medical and psychiatric interviews, a
physical examination, electrocardiogram (ECG), and blood tests. Participants will then be
randomly assigned to receive either paroxetine plus clonazepam or paroxetine plus placebo
(an inactive pill) for 12 weeks. Participants will have weekly clinic visits during which
symptoms and drug side effects will be checked and an interview to evaluate panic disorder
and depression symptoms will be conducted.
The main goal of treatment in patients with Panic Disorder (PD) is to effect a rapid
reduction in symptom severity and improve functioning. While numerous pharmacological
approaches have been used to treat PD, these treatments are limited by variable response
rates, up to a 6-week lag period prior to the onset of clinical response, and sub-optimal
side effect profile, including possible worsening of anxiety and insomnia.
There is recent evidence that the benzodiazepine clonazepam prescribed with selective
serotonin reuptake inhibitors (SSRI) can facilitate a rapid reduction of symptoms in PD. The
improvement in symptoms was maintained despite tapering the clonazepam prior to the end of
the study. However, it was unclear if co-morbid depression influenced the treatment response
to this regimen. In addition, a recent study in patients with major depression demonstrated
that combined fluoxetine-clonazepam treatment resulted in a more rapid antidepressant
response than the fluoxetine-placebo combination.
The proposed study will examine whether combined treatment with a clonazepam and paroxetine
in patients with PD and comorbid depression will accelerate the onset of clinical response
at both panic and depression symptoms. PD with comorbid major depression is a more severe
disorder than PD alone. We will also examine whether the rapid and clinically meaningful
benefits will be sustained until the end of the study, despite tapering off clonazepam at
the midpoint of the study. If this study turns out to be the case combined
SSRI-benzodiazepine treatment may become a standard initial therapeutic approach to PD and
comorbid major depression.
Patients with a primary diagnosis of Panic Disorder without Agoraphobia or Panic Disorder
with Agoraphobia according to DSM-IV criteria, and co-morbid major depressive disorder are
eligible. Patients are required to have a weekly panic attack frequency of greater than or
equal to 1/ week in the month prior to intake or a CGI score greater than 4 in the week
prior to randomization. Patients with co-morbid major depressive disorder will be included
provided that the onset of PD was earlier than the onset of the depressive disorder. The
presence of co-morbid depression will be determined by using DSM-IV criteria for major
depressive disorder, and HDRS scores will be in the moderately-to-severely depressed range
(greater than 15).
Subjects will be at least 18 years old. Those above age 65 years must be able to tolerate
paroxetine starting dose of at least 20 mg daily and be without hepatic or renal
Male and female subjects will be included.
The patient must have given written informed consent prior to any study procedures.
In addition, eligible patients must be in good physical health as confirmed by a complete
physical exam (including normal vital signs), electrocardiogram, neurological exam, and
routine laboratory tests of blood and urine.
Patients will be drug free for at least 7 days when starting with the study medication. We
will study both, untreated, symptomatic patients, and patients who did not respond to
their pervious psychopharmacological treatment. The unsuccessful medication will be
tapered off, and a medication-free period of 7 days will be established.
Patients with any serious or unstable medical disorder or condition that would preclude
the administration of paroxetine or clonazepam (e.g. epilepsy, severe head injury,
meningitis, allergic to either drug).
Patients who would be unable to comply with study procedures or assessments.
Patients who meet DSM-IV lifetime criteria for benzodiazepine abuse or dependence.
Patients who are on other psychotropic drugs must have discontinued them for at least 1
week prior to randomization. Patients are ineligible who experience any current signs of
symptoms of drug withdrawal during taper of unsuccessful medication.
Patients who are currently at high risk for homicide or suicide.
Patients who had previously failed an adequate trial of paroxetine or clonazepam.
Women of childbearing potential who are not practicing a clinically accepted method of
contraception or who have a positive pregnancy test or who are lactating.
Patients who are currently treated with fluoxetine.