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.

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.

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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.

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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.

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.

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.