Panic attacks are often seen in patients with schizophrenia.1 Benzodiazepines and selective serotonin reuptake inhibitors have been reported to produce good results in treating panic attacks in patients with anxiety disorder.2 However, there are few reports about pharmacological treatment for panic attacks in schizophrenic patients.3
Recently, atypical antipsychotics, including olanzapine and risperidone, have been reported to deliver greater therapeutic activity in anxiety symptoms accompanying schizophrenia than conventional antipsychotics such as haloperidol.4,5 Therefore, these atypical antipsychotics may have possible beneficial effect on schizophrenic patients suffering from panic attacks. Previously, we reported a schizophrenic patient with treatment-refractory panic attacks who responded well to switching to risperidone from haloperidol.6 Etxebeste et al. described two patients with panic disorder, not schizophrenia, in whom olanzapine therapy resulted in full suppression of their panic attacks.7
In this report, we describe three schizophrenic patients in whom panic attacks completely disappeared after switching to quetiapine, an atypical antipsychotic, from their ongoing antipsychotics, which included bromperidol, haloperidol and risperidone. To our knowledge, this is the first such report in the literature suggesting a favorable response to quetiapine in panic attacks.
Ms. A was a 40-year-old woman with a 10-year history of schizophrenia. Two years prior to this report, she began experiencing panic attacks that were followed by similar episodes at a frequency of three to four times a month, without deterioration of psychotic symptoms. Consequently, she had to quit her part-time job at a supermarket. Alprazolam 1.2 mg/day was added to her ongoing medication that included bromperidol 9 mg/day and biperiden 3 mg/day, resulting in a period of partial amelioration of her panic attacks. Subsequently, however, she developed anticipatory anxiety and avoidant behaviors. A 50 mg/day dose of fluvoxamine was added to her medication. The dose of fluvoxamine was increased to 200 mg/day for 4 weeks, and the dose of alprazolam remained at 1.2 mg/day. Her clinical symptoms, however, did not improve. Fluvoxamine was gradually withdrawn, and we decided to switch her antipsychotic from bromperidol to quetiapine. Quetiapine 100 mg/day was initiated and titrated up to 400 mg/day for 4 weeks, leading to marked improvement of her panic attacks. Alprazolam was successfully then withdrawn from her medication. Ms. A has been able to go outside without anxiety and resume her part-time job. Her recovery was maintained at a 13-month follow-up.
Mr. B was a 29-year-old man with a 2-year history of schizophrenia. His psychotic symptoms, which included auditory hallucinations, ideas of reference, and delusions of thought insertion, had been well controlled for more than 1 year with haloperidol 12 mg/day and biperiden 6 mg/day. Although he was unable to obtain employment for 2 years due to a number of negative symptoms, he often helped with housework. On September 9, 2000, he suddenly had a panic attack characterized by cardiac palpitations, tachycardia, and fear of dying. He came to the emergency unit of our hospital, received alprazolam 1.2 mg/day, and was discharged. The symptoms resolved, but after several days, the panic attacks recurred without emergence of psychotic symptoms. Two weeks later, he returned to our department with severe panic attacks, for which intramuscular injection of diazepam 10 mg was needed. To enable him to better cope with the panic attacks, the dose of alprazolam 1.2 mg/day was gradually increased to 3.6 mg/day, resulting in good clinical response. However, he discontinued treatment with alprazolam due to sedation. We decided to switch his antipsychotic from haloperidol to risperidone. We decreased the dose of haloperidol, while simultaneously increasing the dose of risperidone. Four weeks later, haloperidol was completely replaced by risperidone 10 mg/day. His panic attacks subsided during this switching period of 4 weeks, however, he developed orthostatic hypotension with symptoms such as dizziness and near-syncope 2 days after starting risperidone monotherapy. Risperidone was then switched to quetiapine, which was increased to 300 mg/day. Irritability experienced at the initial phase of quetiapine treatment spontaneously disappeared. At a 10-month follow-up, Mr. B remained virtually symptom-free, aside from a few disturbances such as diminished emotional expressions and low productivity of speech.
Ms. C was a 26-year-old woman with a 1-year history of schizophrenia. Her clinical condition had been well controlled with risperidone 10 mg/day and biperiden 3 mg/day. Additionally, she was prescribed brotizolam 0.5 mg for sleep disturbance. She had engaged in agriculture, working in a rice field and at a fruit farm. In August of 2000, she suddenly experienced a state of alarm, demonstrating marked anxiety, chest discomfort, shortness of breath, and a fear of losing control, without deterioration of her psychotic symptoms. She came to our hospital and was prescribed alprazolam 1.2 mg/day. The frequency of the panic attacks, however, increased progressively, reaching a pattern of short, successive bursts. Although the dose of alprazolam was increased to 2.4 mg/day, with partial response to her panic attacks, she began to experience anticipatory anxiety without agoraphobia and had to discontinue working. The increase in fluvoxamine up to 200 mg was ineffective, so we decided to withdraw fluvoxamine while keeping the dose of alprazolam 2.4 mg/day and switch her antipsychotic from risperidone to quetiapine, which was gradually increased to 300 mg/day and lead to complete remission of the panic attacks. We then could successfully discontinue alprazolam, and she could resume her work as a farmer. Ms. C's good clinical condition was sustained at 8-month follow-up.
In the Epidemiologic Catchment Area Program of the National Institute of Mental Health survey, panic attacks occurred in 28% to 63% of individuals with schizophrenia.1 However, little is known about the preferable pharmacological strategy in the treatment of schizophrenic patients with panic attacks. We have described three schizophrenic patients with panic attacks who responded well to switching to quetiapine from their ongoing antipsychotics such as bromperidol (Case 1), haloperidol (Case 2) and risperidone (Case 3). In Case 2, quetiapine was switched from risperidone, not haloperidol, for practical purposes. However, risperidone monotherapy was continued for 2 days only due to a side effect. Therefore, it is appropriate that the patient benefited from the switch to quetiapine from haloperidol. In this case, the only reason for discontinuation of risperidone was a side effect, not the lack of risperidone's effect on panic attacks. Although the duration of risperidone monotherapy in this patient is too short to confirm the efficacy of risperidone on panic attacks, it is possible that risperidone treatment would have produced a continuous good response if longer duration of treatment had been allowed.
It would have been more beneficial if the symptomatology expressed by the patients could have been assessed in a more objective way. Unfortunately, we did not observe the patients' panic attacks and psychotic symptoms by using a number of scaling methods, thus being unable to describe accurately the relationship between them. In our clinical impression, however, panic attacks either developed or disappeared without relation to the worsening or improvement of psychotic symptoms in our three patients.
There are some reports suggesting possible association between hyperactivity of intracerebral noradrenergic neurons and the occurrence of panic attacks.8 On the basis of the results of animal experiments, Iruela et al. reported that dopaminergic neurons inhibit the activity of noradrenergic neurons of locus coeruleus, the major brain noradrenalin containing nucleus. Irueda et al. hypothesized that a decline of the dopamine neuron activity leads to hyperactivity of noradrenergic neurons, causing panic attacks.9 In human studies, there are some reports supporting this hypothesis. Argyle et al. reported that panic attacks were found in seven out of 20 patients with schizophrenia, who were undergoing long-term neuroleptic treatment, and two patients experienced worsening of panic attacks with the re-introduction or increase of neuroleptics.10 Higuchi et al. suggested that the dose of neuroleptics tended to be higher in schizophrenic patients with panic attacks than those without it.11 Vazques et al. reported that, in Parkinson’s Disease patients, panic attacks were observed at a high frequency in the "off" state of the "on-off" phenomena during long-term L-dopa treatment, and introduction of bromocriptine, a dopamine-2 agonist, was effective for panic attacks in some patients.12 According to the reports described above, panic attacks may easily develop in schizophrenic patients who have hypofunction of dopamine neurons due to treatment with antipsychotics that have high potentency dopamine antagonistic properties.
At a dose of 300 mg or more, quetiapine has shown much lower dopamine-2 (D2) receptor blockade than haloperidol and risperidone at clinically effective doses in position emission tomography (PET) studies, while demonstrating sufficient antipsychotic effects.13,14 Therefore, switching to quetiapine may release dopamine neurons from excessive inhibition induced by strong dopamine antagonists such as bromperidol, haloperidol, and risperidone, resulting in suppression of panic attacks in our patients. However, the exact mechanism that may account for quetiapine's antipanic effects is unclear because clozapine, which also has a low D2 blockade similar to quetiapine, has been reported to cause panic attacks in patients with schizophrenia.15
Although this report should be considered preliminary, given the promising results of our cases, further study should be conducted to examine the beneficial effect of quetiapine in schizophrenic patients with treatment-refractory panic attacks.