Abstract
Introduction
Panic disorder occurs in up to 3% of the adult population at some time, and is associated with other psychiatric and personality disorders, and with drug and alcohol abuse. The risk of suicide and attempted suicide has been found to be higher in people with panic disorder than in people with other psychiatric illness, including depression.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug treatments for panic disorder? What are the effects of drug treatments for panic disorder? What are the effects of combined drug and psychological treatments for panic disorder? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 36 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: applied relaxation; benzodiazepines; breathing retraining; brief dynamic psychotherapy; buspirone; client-centred therapy; cognitive behavioural therapy (CBT) (alone or plus drug treatments); cognitive restructuring; couple therapy; exposure (external or interoceptive); insight-orientated therapy; monoamine oxidase inhibitors (MAOIs); psychoeducation; selective serotonin reuptake inhibitors (SSRIs); self-help; and tricyclic antidepressants (imipramine).
Key Points
Panic disorder is characterised by recurrent, unpredictable panic attacks, making people worry about or change their behaviour to avert subsequent panic attacks or their consequences.
Panic disorder occurs in up to 3% of the adult population at some time, and is associated with other psychiatric and personality disorders, and with drug and alcohol abuse.
The risk of suicide and attempted suicide has been found to be higher in people with panic disorder than in people with other psychiatric illness, including depression.
CBT is effective in reducing symptoms of panic disorder over 6 months or longer, but we don't know whether it is more effective than other psychological treatments.
CBT is more effective than waiting list and other controls in reducing symptoms in panic disorder with or without mild to moderate agoraphobia.
We don't know whether CBT alone is more effective than antidepressants alone, but weak evidence suggests that the effects of CBT may last longer. Combined treatment with CBT plus antidepressants has shown to be more effective than CBT alone or antidepressants alone in reducing symptoms in the short term.
Other forms of psychotherapy can also be beneficial in reducing symptoms associated with panic disorder, with or without drug treatments.
Applied relaxation, client-centred therapy, cognitive restructuring, and exposure to the panic-inducing stimulus are all likely to be effective in reducing symptoms.
Self-help using CBT techniques may be as effective as therapist-based CBT.
Breathing retraining, couple therapy, insight-orientated therapy, psychoeducation, and brief dynamic psychotherapy may be beneficial, but we found insufficient evidence to be sure.
SSRIs and tricyclic antidepressants are also effective at reducing the symptoms of panic disorder.
Benzodiazepines can be effective in reducing symptoms in panic disorder, but their adverse-effect profile makes them unsuitable for long-term treatment.
About this condition
Definition
A panic attack is a period in which there is sudden onset of intense apprehension, fear, or terror, often associated with feelings of impending doom. Panic disorder is classified by the DSM-IV as recurrent, unpredictable panic attacks followed by at least 1 month of persistent concern about having another panic attack, worry about the possible implications or consequences of the panic attacks, or a significant behavioural change related to the attacks. The term “panic disorder” excludes panic attacks attributable to the direct physiological effects of a general medical condition, a substance, or another mental disorder. The ICD-10 classifies panic disorder as recurrent, unpredictable panic attacks, with sudden onset of palpitations, chest pain, choking sensations, dizziness, and feelings of unreality, often with associated fear of dying, losing control, or going mad, but without the requirement for the symptoms to have persisted for 1 month or longer. The DSM-IV classifies these conditions as primarily panic disorder with or without agoraphobia, whereas the ICD-10 classifies them as primarily agoraphobia with or without panic disorder. The diagnosis should not be made in people with co-morbid depression, when the panic is considered to be secondary to depression. Diagnosis: Although panic attacks are a necessary feature of panic disorder, panic attacks on their own are not enough to make the diagnosis. Panic attacks may happen in the context of specific situations such as social or specific phobia which are different from panic disorder. A diagnosis of panic disorder is made in the presence of recurrent unexpected panic attacks followed by at least 1 month of persistent concern about having another panic attack.
Incidence/ Prevalence
Panic disorder often starts at about 20 years of age (between late adolescence and the mid-30s). Lifetime prevalence is 1% to 3%, and panic disorder is more common in women than in men. An Australian community study found 1-month prevalence rates for panic disorder (with or without agoraphobia) of 0.4% using ICD-10 diagnostic criteria, and of 0.5% using DSM-IV diagnostic criteria. One systematic review of observational data estimated the prevalence rate of panic disorder during the perinatal period at between 1.3% to 2.0%, and that, although the symptoms of panic during pregnancy may be identical to at other periods, they are often interpreted in the context of the perinatal state (e.g., a woman may interpret panic attacks during pregnancy as an indication that something is wrong with the pregnancy).
Aetiology/ Risk factors
The onset of panic disorder tends to be preceded by stressful life events, although a negative interpretation of these events, in addition to their occurrence, has been suggested as an important causal factor. Panic disorder is associated with major depression, social phobia, generalised anxiety disorder, obsessive compulsive disorder, and a substantial risk of drug and alcohol misuse. It is also associated with avoidant, histrionic, and dependent personality disorders.
Prognosis
The severity of symptoms in people with panic disorder fluctuates considerably, and people commonly have periods of no attacks, or only mild attacks with few symptoms. There is often a long delay between the initial onset of symptoms and presentation for treatment. Recurrent attacks may continue for several years, especially if associated with agoraphobia. Reduced social or occupational functioning varies among people with panic disorder, and is worse in people with associated agoraphobia. Panic disorder is also associated with an increased rate of attempted suicide, with one study finding that it occurred in 20% of people with panic disorder, compared with 12% of people with panic attacks alone, 6% of those with other psychiatric disorder, and 1% of those with no disorders. The odds ratio for attempted suicide was increased if there were co-morbid conditions. One study analysing data from RCTs and systematic reviews found that co-existence of anxiety and depressive features adversely affected treatment response at 12 years compared with treatment of panic disorder alone.
Aims of intervention
To reduce the severity and frequency of panic attacks, phobic avoidance, and anticipatory anxiety; to improve social and occupational functioning, with minimal adverse effects of treatment.
Outcomes
Symptom severity measures of panic attacks, agoraphobia, and associated disability (self-reported and clinician-rated, before and after treatment, and longer term) using general or specific scales for panic disorder (e.g., the Panic and Agoraphobia Scale, the Mobility Inventory for Agoraphobia), relapse rates; quality of life; and adverse effects.
Methods
Clinical Evidence search and appraisal June 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2007, Embase 1980 to June 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for assessment in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people of whom more than 80% were followed up for a minimum of 6 months. We excluded all studies described as “open”, “open label”, or not blinded unless blinding was not possible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. This review includes RCTs in people aged 18 to 65 years old, and excludes RCTs in people solely with the co-morbidity of head injury and organic brain disorder, or people solely with phobic avoidance of social phobia (i.e., social phobia without panic disorder). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Panic disorder.
| Important outcomes | Adverse effects, Quality of life, Symptom severity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of non-drug treatments for panic disorder? | |||||||||
| at least 45 controlled studies (not clear) | Symptom severity | CBT versus placebo or no treatment | 4 | –3 | –1 | –1 | 0 | Very low | Quality points deducted for unclear randomisation, inclusion of studies other than RCTs, weak methods, and incomplete reporting of results. Consistency point deducted for conflicting results (depression). Directness point deducted for unclear outcome assessment |
| not clear (not clear) | Quality of life | CBT versus placebo or no treatment | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for unclear randomisation, inclusion of studies other than RCTs, weak methods, and incomplete reporting of results. Directness point deducted for unclear outcome assessment |
| at least 17 clinical studies (not clear) | Symptom severity | CBT versus antidepressants | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for inclusion of studies other than RCTs, incomplete reporting of results, and uncertainty about significance of result (publication bias). Directness points deducted for inclusion of people taking benzodiazepines and unclear outcome assessment |
| 26 controlled studies (not clear) | Symptom severity | CBT versus behavioural therapy | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for inclusion of studies other than RCTs, and incomplete reporting of results. Directness point deducted for unclear outcome assessment |
| 26 controlled studies (not clear) | Quality of life | CBT versus behavioural therapy | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for inclusion of studies other than RCTs, and incomplete reporting of results. Directness point deducted for unclear outcome assessment |
| 1 (73) | Symptom severity | CBT versus exposure | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and combining active treatment groups in statistical analysis |
| 2 (96) | Symptom severity | Applied relaxation versus waiting list control | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and baseline differences between groups. Directness point deducted for composite outcome |
| 5 (279) | Symptom severity | Applied relaxation versus CBT | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for co-intervention (self-exposure instructions) |
| 1 (32) | Symptom severity | Applied relaxation versus drug treatments | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (108) | Symptom severity | Client-centred therapy versus client-centred therapy plus exposure | 4 | –2 | –1 | –2 | 0 | Very low | Quality points deducted for sparse data, and incomplete reporting of results. Consistency point deducted for different results for different outcomes. Directness points deducted for inclusion of people with different disease severity and unclear outcome assessment |
| unclear (unclear) | Symptom severity | Cognitive restructuring plus interoceptive exposure compared with waiting list, pill placebo, or psychological placebo | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for incomplete reporting of results, and unclear reporting of studies included in analysis. Directness points deducted for inclusion of co-intervention and unclear outcome assessment |
| at least 1 (at least 28) | Symptom severity | Cognitive restructuring versus exposure | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for incomplete reporting of results, and unclear reporting of studies included in analysis. Directness points deducted for no direct statistical analysis between groups in one analysis and unclear outcome assessment in review |
| at least 2 (at least 234) | Symptom severity | Exposure versus control | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, and unclear reporting of studies included in analysis in one review. Directness points deducted for co-intervention in placebo group (relaxation therapy) |
| at least 8 clinical/controlled studies (not clear) | Symptom severity | Self-help methods versus no treatment | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for inclusion of non-RCT data, incomplete reporting of results, and unclear reporting of studies included in analysis. Directness point deducted for combined control group (no treatment, pill, or therapy placebo) |
| 3 (107) | Symptom severity | Self-help methods versus CBT | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, inclusion of non-RCT data in analysis, and unclear reporting of studies included in analysis. Directness points deducted for no direct statistical comparison between groups in two studies |
| 1 (45) | Symptom severity | Breathing retraining plus CBT versus control | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, and incomplete reporting of results. Directness point deducted for inclusion of co-intervention (CBT) |
| 1 (45) | Symptom severity | Breathing retraining plus CBT versus CBT alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data, and incomplete reporting of results |
| 1 (40) | Symptom severity | Brief dynamic psychotherapy plus clomipramine versus clomipramine alone | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, and incomplete reporting of results. Directness point deducted for no statistical comparison between groups for some outcomes |
| 1 (49) | Symptom severity | Panic-focused psychodynamic psychotherapy versus applied relaxation | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, and incomplete reporting. Directness point deducted for high rate of dropout in one group (significantly higher than other group) |
| 3 (82) | Symptom severity | Different forms of couple therapy versus each other | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data, and incomplete reporting of results |
| What are the effects of drug treatments for panic disorder? | |||||||||
| 92 controlled studies, of which at least 2 were RCTs (at least 461) | Symptom severity | SSRIs versus placebo | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for incomplete reporting of results, inclusion of non-RCT data, and unclear reporting of studies included in analysis. Directness points deducted for use of treatment responders in one RCT, unclear measurement of outcome, and no direct statistical analysis between groups in some studies |
| 91 controlled studies, of which at least 2 were RCTs (unclear, at least 237) | Symptom severity | Tricyclic antidepressants versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, inclusion of non-RCT data, and unclear reporting of studies included in analysis. Directness point deducted for no statistical comparison between groups in some studies |
| At least 89 controlled studies, of which at least 17 were RCTs (at least 2284) | Symptom severity | Benzodiazepines versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, inclusion of non-RCT data, and unclear reporting of studies included in analysis. Directness point deducted for no statistical comparison between groups in some studies |
| 2 (89) | Symptom severity | Oral buspirone plus CBT versus placebo plus CBT | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results |
| 1 (366) | Symptom severity | MAOIs versus SSRIs | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for small number of comparisons |
| What are the effects of combined drug and psychological treatments for panic disorder? | |||||||||
| at least 9 RCTs (at least 709) | Symptom severity | CBT plus antidepressants versus CBT alone | 4 | –3 | –1 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, unclear reporting of studies included in one analysis, inclusion of behavioural therapy in one analysis, and possible publication bias. Consistency point deducted for inconsistent results with different outcomes and over different time periods. Directness point deducted for limited generalisability |
| 20 studies (not clear) | Quality of life | CBT plus antidepressants versus CBT alone | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results, unclear reporting of studies included in analysis, inclusion of behavioural therapy, and possible publication bias |
| 6 (604) | Adverse effects | CBT plus antidepressants versus CBT alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deduced for combined analysis in control group. Directness point deducted for generalisability of results |
| at least 10 RCTs (at least 336) | Symptom severity | CBT plus antidepressants versus antidepressants alone | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, inclusion of co-intervention (benzodiazepines) in one study. Directness point deducted for limited generalisability |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Applied relaxation
A technique involving training in relaxation techniques and self-monitoring of symptoms without challenging beliefs.
- Beck Depression Inventory
Standardised scale to assess depression. This instrument consists of 21 items to assess the intensity of depression. Each item is a list of 4 statements (rated 0, 1, 2, or 3), arranged in increasing severity, about a particular symptom of depression. The range of scores possible are 0 = least severe depression to 63 = most severe depression. It is recommended for people aged 13 to 80 years. Scores of more than 12 or 13 indicate the presence of depression.
- Behavioural therapy
is a type of psychotherapy which is aimed at modifying the behaviour causing distress or impairment, by focusing on the environment and context in which the behaviour occurs. Unlike other psychotherapies, behavioural therapy doesn’t endorse mind–body split or the impact of past developmental issues, and treats the person as a unit.
- Client-centred therapy
A system of psychotherapy based on the view that the client has the internal resources to improve and is in the best position to resolve his or her own personality dysfunction. It has roots in psychoanalysis and sees clients as taking a more active role in their treatment.
- Clinical Global Impression Scale
A one-item, observer-rated scale for measuring the severity of a condition. It has been investigated for validity and reliability. The scale is scored from 0 (not ill at all) to 7 (severely ill).
- Cognitive behavioural therapy (CBT)
Brief structured treatment using relaxation and exposure procedures, and aimed at changing dysfunctional beliefs and negative automatic thoughts (typically 20 sessions over 12–16 weeks).
- Cognitive restructuring
An intervention that involves asking questions to help people challenge the stereotyped and repetitive thoughts and images that enhance fear.
- Couple therapy
An intervention that involves using significant relationships to help change previous persistent and inflexible patterns of behaviour.
- Exposure
A type of behavioural therapy involving deliberate exposure to previously avoided situation or feared stimuli (including thoughts). It can be done by either asking the person to imagine being in the previously avoided situation, especially when direct exposure is impractical or difficult (such as when a person has a fear of flying) — termed in vitro, interoceptive, or imaginal exposure. Alternatively, exposure can be in vivo or exteroceptive, in which exposure is to real life situations or stimuli.
- Hamilton Anxiety Rating Scale
A 14-item observer-rated scale for measuring the severity of anxiety. It has been investigated for validity and reliability. Each item is rated on a 5-point scale from 0 (no symptoms) to 4 (severe or grossly disabling symptoms). Total score ranges from 0 to 56, with 14 or higher indicating clinically significant anxiety.
- Hamilton Depression Rating Scale
a measure of depressive symptoms using 17 items, with total scores from 0 to 54 (higher scores indicate increased severity of depression).
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Psychoeducation
An intervention aimed at educating the person with psychiatric disorder in subject areas that serve the goals of treatment and rehabilitation.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Shailesh Kumar, Division of Psychiatry, Auckland Medical School, Auckland, New Zealand.
Darren Malone, Rotorua Hospital, Rotorua, New Zealand.
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