Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia.

OBJECTIVE: To establish whether the combination of cognitive-behavioral therapy (CBT) and pharmacotherapy (SSRI) was more effective in treating panic disorder (PD) than either CBT or SSRI alone, and to evaluate any differential effects between the mono-treatments. METHOD: Patients with PD (n = 150) with or without agoraphobia received CBT, SSRI or CBT + SSRI. Outcome was assessed after 9 months, before medication taper. RESULTS: CBT + SSRI was clearly superior to CBT in both completer and intent-to-treat analysis (ITT). Completer analysis revealed superiority of CBT + SSRI over SSRI on three measures and no differences between CBT and SSRI. ITT analysis revealed superiority of SSRI over CBT on four measures and no differences between CBT + SSRI and SSRI. CONCLUSION: Both the mono-treatments (CBT and SSRI) and the combined treatment (CBT + SSRI) proved to be effective treatments for PD. At post-test, CBT + SSRI was clearly superior to CBT, but differences between CBT + SSRI and SSRI, and between SSRI and CBT, were small.

Five-minute recordings of heart rate variability in obsessive-compulsive disorder, panic disorder and healthy volunteers.

BACKGROUND: Recent studies have used spectral analysis of heart rate variability (HRV) to study autonomous nervous system (ANS) function in panic disorder (PD). Most studies reported a reduced HRV in resting PD patients, suggesting increased sympathetic and decreased parasympathetic tone. In obsessive-compulsive disorder (OCD) inconsistent findings have been reported on ANS function and to date no studies have been carried out with spectral analysis of HRV. In this HRV study we compared ANS function in patients with PD, OCD and normal controls. METHODS: Standardized HRV measurement was carried out in 24 PD patients, 26 OCD patients and 24 age-matched normal controls. All patients were drug free. As this comparison yielded unexpected results, the PD and normal control samples were enlarged to 53 and 54 subjects, respectively, to verify our first measurement. RESULTS: OCD patients were not characterized by a reduced HRV, as compared to normal controls. This was also found in PD patients, even in the enlarged sample. CONCLUSIONS: HRV analysis in patients with OCD or PD showed that these patients were not characterized by ANS abnormalities, as no evidence was found of diminished HRV in a large sample of resting OCD and PD patients, measured sitting on a hospital bed.

Heart rate variability as predictor of nonresponse to mirtazapine in panic disorder: a preliminary study.

Using spectral analysis of heart rate, several studies have shown that panic disorder patients are characterized by a reduced heart rate variability (HRV), indicative of abnormalities in autonomous nervous system (ANS) function. We recently reported that patients with panic disorder, who did not respond to pharmacotherapy, were characterized at baseline by a higher heart rate. In this study, ANS functioning is investigated as a possible predictor of nonresponse to pharmacotherapy. Twenty-eight medication-free panic disorder patients entered a 12-week open-label treatment study with mirtazapine. Five-minute HRV recordings were obtained before treatment and were analysed using spectral analysis. The data of 17 patients could be used. The total spectrum and low frequency power of responders to mirtazapine were significantly higher than those of nonresponders. Our findings suggest that nonresponders to short-term mirtazapine treatment are characterized at baseline by a lowered output of the ANS. The results are preliminary in view of the small sample studied.

The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period.

In this open label pilot study, we studied the efficacy of mirtazapine (Remeron) in panic disorder. Twenty-eight patients with a DSM-IV diagnosis of panic disorder, with or without agoraphobia (10 males/18 females), were included and 19 patients completed the study. The 15-week trial started with a 3-week single-blind placebo run-in period. After this run-in period, the 12-week active treatment phase started. As primary efficacy measures, we studied the decrease in the number of full symptom panic attacks and the number of patients completely free of panic during the last 3 weeks of the study. Seventy-four percent of the patients were considered responders, according to a decrease of at least 50% in panic attack frequency. All primary and secondary efficacy measures showed a significant improvement from the second week of active treatment onwards to endpoint. The main side-effects were different from the usual side-effects in selective serotonin reuptake inhibitors (SSRIs) (initial drowsiness, weight gain and pain in the legs). The results of this open label study in panic disorder suggest that mirtazapine seems to be a fast and effective treatment alternative for SSRIs in panic disorder.

The prediction of nonresponse to pharmacotherapy in panic disorder: a review.

Several effective pharmacotherapeutic treatments exist for panic disorder; however, not all patients respond to treatment: between 20% to 40% are non-responders. Recent studies have reported several predictors of nonresponse to pharmacotherapy. In this review two questions are addressed: is there consensus with respect to predictors of nonresponse and are there any differences between short-term and long-term predictors? In this review both short-term and long-term outcome studies are discussed. Studies were included if at least DSM-III criteria were used and baseline variables were investigated as possible predictor of response, or nonresponse, to pharmacotherapy. Of each clinical predictor, tallies were made of the particular predictors employed and of those predictors that predicted nonresponse. It appears that a long duration of illness and severe agoraphobic avoidance are robust predictors of nonresponse, particularly in long-term studies. Personality disorders, or even personality traits, are possibly the most robust predictors of nonresponse. Several factors appear to be robust predictors of nonresponse: factors that are present before treatment and exert their influence on short-term and long-term treatment outcome. Prospective studies are needed to further investigate these factors and to test whether it is viable to intervene in an attempt to increase treatment response.

Review of current treatment in panic disorder.

The ideal properties for an antipanic agent include the ability to provide complete recovery from panic attacks, resolution of associated anxiety and avoidance behavior, relapse prevention, good tolerability, and efficacy in comorbid conditions including depression. We compared the properties of currently available treatment options for panic attacks, including the benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRIs), with this ideal. Experimental approaches in the development of therapeutic agents of potential use against panic disorder were also examined. It is clear that SSRIs, such as paroxetine, are an effective treatment for panic disorder, and their antidepressant activity also allows concurrent treatment of comorbid depressive disorders, for which patients with panic disorder are at high risk. However, despite the availability of effective antipanic agents, some patients do not respond to treatment.

Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacks.

Data from animal studies suggest a functional relationship between the cholecystokinin-ergic (CCK) and the serotonergic (5-HT) system. There is increasing evidence that the cholecystokinin-4 (CCK4) challenge test could be a valid experimental model for panic attacks in man. The aim of the present study is twofold; 1) to validate this model further and 2) to shed more light on the putative CCK/5-HT interaction. To this end, we studied the effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on CCK4-induced panic attacks. Twenty-six panic disorder (PD) patients received, before and after a double blind 8-week treatment period with fluvoxamine (n = 17) or placebo (n = 9), a single blind bolus injection with 50 micrograms CCK4. Treatment with fluvoxamine (150 mg daily) significantly decreased the sensitivity of PD patients for CCK4 while placebo was without effect. Of the patients who responded to treatment, 83% no longer experienced a panic attack when rechallenged with CCK4, whereas in the non-responders group this was only 28%. In the fluvoxamine group the treatment response evaluated by the Hamilton Anxiety Scale (HAS) showed a statistically significant treatment effect. The results of this study strengthen the validity of the CCK4 test as an experimental human model for panic attacks and yield evidence supporting the hypothesis that both CCK and serotonin are implicated in the regulation of anxiety.

The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients.

The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two different dosages of CI-988 (50 mg or 100 mg) or placebo 2 h prior to an IV bolus injection of CCK4 (20 micrograms) on two separate occasions. The primary efficacy parameter was the total intensity score on the Panic Symptoms Scale (PSS). Secondary parameters were the number of panic symptoms, time to and occurrence of the first panic symptoms, duration of symptoms, intensity of apprehension and the percentage of patients who did not have a panic attack. The PSS failed to show a statistically significant treatment effect on any of these outcome measures. The average panic rate was 50%, 14.3% and 37.5% after placebo, 50 and 100 mg CI-988, respectively. The differences in panic rate were not statistically significant. The results of this study suggest that CI-988 in doses up to 100 mg is not effective in reducing symptoms of panic anxiety induced by CCK4.

MHPG and heart rate as correlates of nonresponse to drug therapy in panic disorder patients. A preliminary report.

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse.

A double-blind comparative study of brofaromine and fluvoxamine in outpatients with panic disorder.

Previous studies have shown that both selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorders (PD). In this study, the SSRI fluvoxamine (Fluv) was compared with the MAO-A-I brofaromine (Brof). Thirty patients with the diagnosis of PD with or without agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment, 93% of the Brof group and 87% of the Fluv group considered themselves much or very much improved. Taking a reduction in the Hamilton Rating Scale for Anxiety score of 50% or more, 33% of the Fluv patients and 47% of the Brof patients were responders to treatment. After an increase in anxiety in the 1st week, which was more severe in Fluv-treated patients than for Brof, a clinically relevant decrease in anxiety symptoms and reduction in panic attacks and avoidance behavior was observed. There was no significant difference between the treatment groups. The most prominent side effects were middle-sleep disturbance (Brof), tiredness (Fluv), and nausea after taking the medication (Brof and Fluv). During a double-blind follow-up period of another 12 weeks, a further improvement was found in both treatment groups without significant differences between the two groups. The selective and reversible MAO-A-I brofaromine and the SSRI fluvoxamine are equally effective in the treatment of PD. Both compounds lead to a reduction in the number of panic attacks and a subsequent reduction in agoraphobic avoidance.

Pentagastrin has panic-inducing properties in obsessive compulsive disorder.

The effects of the CCKB-receptor agonist pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK-4), were studied in seven patients suffering from obsessive compulsive disorder (OCD) and seven healthy controls. All subjects were challenged with an IV dose of 0.6 micrograms/kg pentagastrin or placebo under double blind placebo controlled conditions, on two separate occasions, with a minimum interval of 1 week. Six (86%) out of seven OCD patients experienced a panic-like reaction after pentagastrin administration, against only two (29%) in the control group. These differences failed to reach statistical significance, probably due to the small sample size. No increases were observed in obsessions or compulsive behaviors as assessed with the Yale-Brown Obsessive Compulsive Challenge Scale, neither in the pentagastrin, nor in the placebo condition. These findings suggest that pentagastrin has panic-inducing properties in OCD patients, without affecting the core symptoms. The panic-inducing properties of pentagastrin are not specific for panic disorder patients, which might be indicative of a common neurobiological dysfunction in panic disorder and OCD at the level of CCK-B receptors.

Responders and non-responders to drug treatment in social phobia: differences at baseline and prediction of response.

Differences between responders and non-responders to drug therapy were investigated in social phobia. Two previously published studies were pooled to obtain data of 30 patients who were treated for 12 weeks with brofaromine or fluvoxamine. Four criterion variables were used to divide patients in responders and non-responders. Depending on the criterion variable up to 72% of the patients were regarded as responders. Non-responders differed from responders in that they had a higher heart rate and a higher blood pressure. They were also characterized by higher scores on several psychometric scales, indicative of illness severity.

Behavioral, neuroendocrine and biochemical effects of different doses of 5-HTP in panic disorder.

To investigate the role of serotonin (5-HT) in the pathophysiology of panic disorder (PD) a challenge test with L-5-hydroxytryptophan (5-HTP) was conducted. Seven patients suffering from PD and seven healthy controls received an i.v. challenge with 10 mg, 20 mg and 40 mg 5-HTP and placebo in random order on four different occasions. Before, during and until 2 h after 5-HTP administration anxious and depressive symptomatology was assessed. In addition, plasma levels of 5-HTP, cortisol, and 5-HIAA were measured at several timepoints. During and after infusion of placebo or any of the different dosages of 5-HTP, none of the patients or controls experienced a panic attack or showed an increase in anxiety or depressive symptoms. There was a dose-related increase in side effects, like nausea, dizziness and fatigue. Only infusion with 40 mg 5-HTP led to an increase in plasma cortisol in both patients and controls. The observed increase in plasma cortisol level was higher for patients compared to controls only at 30 min after infusion. In conclusion, stimulation of the serotonergic neuronal system by three different dosages of 5-HTP did not induce panic or anxiety in PD patients and healthy controls. The 5-HT hypersensitivity hypothesis of PD could not be confirmed in the present study.

The prediction of response in the anxiety disorders.

In this review the results are discussed on the prediction of response to pharmacotherapy in panic disorder (PD) and social phobia (SP). From the literature it appears that in PD variables indicative of illness severity are predictors of non-response. In our own studies we found that non-responders to pharmacotherapy in PD are characterised by a higher score on the Blood-Injury subscale of the Fear Questionnaire, a higher plasma MHPG and a higher heart rate. In SP non-responders to pharmacotherapy were also characterised by a higher heart rate. They also appeared to have a higher blood pressure. Furthermore non-responders to pharmacotherapy in SP had higher scores on several psychometric scales, indicative of illness severity.

Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia.

In the present open study the effects of the D1-dopamine antagonist SCH 39166 on positive and negative symptoms of schizophrenia (DSM-IIIR) were investigated. SCH 39166 was given orally according to a fixed dosage schedule (day 1: 25 mg b.i.d; day 4: 50 mg b.i.d.; day 7: 100 mg b.i.d.; day 18: 200 mg b.i.d.; day 21: 225 mg b.i.d.). Seven patients completed 2 weeks, and five patients completed the study. The reason for premature withdrawal was lack of efficacy or refusal to take SCH 39166. In none of the patients a reduction of the BPRS or CGI score was found. As measured with the PANSS, a significant reduction was observed in the score of the negative subscale, whereas the positive symptoms scale and general psychopathology score remained unaffected. Akathisia, rigidity and hypokinesia were reported occasionally, although only mild in severity. The results of the present study do not support the hypothesis that D1-dopamine antagonists are clinically effective antipsychotics in schizophrenia, considering the fact that SCH 39166 had no effect on positive symptoms. The present study provides circumstantial evidence for an effect of SCH 39166 on negative symptoms.

Phobic symptoms as predictors of nonresponse to drug therapy in panic disorder patients (a preliminary report).

Factors that predict nonresponse to drug therapy (brofaromine or fluvoxamine) were investigated in a sample of 44 panic disorder patients. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment. Using this definition, 15 patients (32.6%) were considered nonresponders. Nonresponders had a higher score on the Blood-Injury subscore of the Fear Questionnaire (FQ) and more often had high scores on several FQ subscores, indicative of comorbid phobic symptoms. These variables were subsequently used to predict nonresponse.