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Psychiatric Times September 2000 Vol. XVII Issue 9

All physicians should be aware of the strong association between suicide attempts and panic disorder, and they should be attentive to the symptoms that are risk factors for a suicide attempt. The alliance between the two afflictions is not merely coincidental; they are related in a very systematic and logical manner. In some instances, the rate of suicide attempts in patients with comorbid panic disorder has been higher than the rate of suicide attempts in patients with major depression (Markowitz et al., 1989).

Quality of Life

In susceptible individuals, panic disorder's debilitating symptoms can lead to major depression. Imagine being constantly plagued by "recurrent, unexpected panic attacks" where there is "intense apprehension, fearfulness or terror, often associated with feelings of impending doom" (American Psychiatric Association, 1994). The symptoms of panic attacks also include dyspnea, palpitations, chest pain or discomfort, a choking or smothering sensation, dizziness, feelings of unreality, paresthesias (numbness or tingling sensations), chills or hot flushes, sweating, faintness, trembling, and a fear of dying or going crazy.

As a result, patients may become reluctant to go outside the home alone or into public places-behaviors associated with agoraphobia. After repeatedly experiencing such uncomfortable symptoms that affect one's ability to function in personal and professional realms, some patients develop major depression.

Not all patients who experience panic attacks suffer from panic disorder; the frequency and intensity of the attacks must first reach a certain severity. According to the APA's Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV), panic disorder is defined as recurrent unexpected panic attacks, with at least one of the attacks being followed by one month (or more) of one or more of the following:

a) persistent concern about having additional attacks;

b) worry about the implications of the attack or its consequences, such as having a heart attack or going crazy;

c) a significant change in behavior related to the attacks. The panic attacks are not due to physiological effects of a substance, a general medical condition or another mental disorder. Panic disorder can occur with or without agoraphobia.

The prevalence of panic disorder with or without agoraphobia over a lifetime has been estimated to be 1.5% and 3.5%, according to the DSM-IV. Panic disorder without agoraphobia is diagnosed twice as often in women as in men, and panic disorder with agoraphobia is diagnosed three times as often in women. While the age of onset varies considerably, it is most typically between late adolescence and the mid-30s.

As previously mentioned, panic disorder is often associated with depression. According to the DSM-IV, major depressive disorder occurs frequently (50% to 65%) in individuals with panic disorder. In one-third of the patients with both disorders, the depression precedes the onset of panic disorder, whereas in the remaining two-thirds, depression occurs coincident with or following the onset of panic disorder. There is also high comorbidity with anxiety disorders. Among individuals with panic disorder, 15% to 30% have comorbid social phobia and 25% have generalized anxiety disorder.

Seeking Medical Attention

Since panic symptoms can mimic those of medical illnesses or co-occur with them, patients with panic disorder often seek medical attention from general physicians and emergency departments (Weissman et al., 1989). Such patients may be misdiagnosed or treated only for coexisting medical conditions.

Patients experiencing panic symptoms often believe they are seriously ill or about to die; many fear they are experiencing a heart attack or another cardiac disorder. An attending physician must examine the patient for cardiac dysfunction.

If no disorder is found, a psychiatric referral should be made so the patient can be thoroughly evaluated for panic disorder. Without such an evaluation, the panic disorder will go untreated, thereby significantly increasing the risk for depression and possibly suicide. If the panic disorder is treated properly, it is likely that the somatic symptoms will disappear and the use of medical services will decrease.

' To evaluate the quality of life experienced by those suffering from panic disorder, Candilis and colleagues (1999) paid particular attention to the influence of anxiety and depression comorbidity in a group of patients.

The presence of panic disorder alone was associated with quality of life disruptions on each of eight subscales of the Medical Outcomes Study Short Form Health Survey (SF-36) as compared to age- and sex-adjusted norms for the general population. The eight subscales included Physical Function, Role-Physical, Body Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health.

The presence of comorbid affective disorder (either major depression or dysthymia) was associated with another significant increment in dysfunction for the Social Function and Mental Health subscales. Similarly, the presence of comorbid anxiety disorders was associated with poorer functioning on the Body Pain and Social Function subscales (Candilis et al., 1999). Proper recognition and treatment of affective and anxiety disorders will ease the dysfunction reported in these subscales and increase the quality of life for these patients.

Risks for Suicide/Substance Abuse

The frequent co-occurrence of panic disorder and alcohol or other drug abuse coupled with depression and/or anxiety can substantially increase the risk for suicide. Patients suffering from panic disorder may begin to use alcohol to avert the discomfort of the panic attacks, but they often become dependent upon it to dull anxiety and the subjective distress associated with the disorder and its comorbid associations.

This form of self-medication is quite common in panic disorder patients (APA, 1994; Munjack and Moss, 1981). Since alcohol is a depressant and an ineffective pharmacological method of controlling panic disorder, the patients may believe their symptoms are worsening. The idea of suicide to end the pain can become attractive.

Lepine and colleagues (1993) looked at suicide attempts in patients with panic disorder and the role of substance abuse. In this study of 100 outpatients with panic disorder, 42% attempted suicide at least once in their lives-11 of the 37 male patients (29.7%) and 31 of the 63 female patients (49.2%) had attempted suicide. All suicide attempts were made by drug overdose. Among the patients, 52% had a history of major depressive episode, and 31% had a lifetime diagnosis of alcohol and/or other substance abuse.

Patients with panic disorder who attempted suicide were significantly more likely to have suffered from major depressive episode and from alcohol and/or other substance abuse in their lifetime than those who did not attempt suicide. Among the 42 suicide attempters in the Lepine et al. study, 30 (71.4%) met DSM-III-R criteria for major depressive episode at least once in their lives, and 19 (45.2%) met criteria for alcohol and/or other substance abuse.

In patients with panic disorder who also had lifetime major depressive episodes and addictive disorders, the prevalence of suicide attempt was higher (72.2%) than for those suffering either from panic disorder and major depressive episode (50%) or panic disorder and alcohol and/or other substance abuse (46.2%). The prevalence of suicide attempt was also much higher than for those with panic disorder who did not suffer from major depression or substance use disorder (17.1%) (Lepine et al., 1993).

Even legally prescribed substances, such as alprazolam (Xanax) have been known to increase the risk of suicide attempt in patients suffering from panic disorder. A triazolobenzodiazepine, alpraz-olam has been found to be efficacious for panic disorder (Ballenger et al., as cited in Kaplan et al., 2000). It is approved and widely used in the United States for panic disorder with or without agoraphobia. However, "potentially serious adverse events, including depression and suicide attempts, have been reported in patients taking this medication," according to Kravitz et al. (1993). "The causal relationship remains unclear and requires further study."

Since treatment with alprazolam is known to help panic disorder symptoms, the prescribing physician must exercise extreme prudence when using this medication to treat a patient suffering from panic disorder and comorbid major depression. The symptoms of panic disorder may be relieved, but alprazolam is not a treatment for depression, and improperly or inadequately treated depression carries the risk of potential suicide. Additionally, alprazolam is associated with a risk of dependence and withdrawal syndromes.

Risks for Suicide/Aggressive Tendencies

Although women are more likely to suffer panic attacks than men are, panic attacks are correlated with aggressive behavior in both sexes (Korn et al., 1997). Individuals often describe a fear of losing control or of performing an uncontrollable act; such fears create another risk for suicide. The possibility of a direct temporal association between panic attacks and inwardly and outwardly directed aggression has received some attention in literature, but for the most part it is overlooked.

Several theoretical viewpoints may shed some light on this close relationship. In a discussion of panic disorder from an evolutionary perspective, Nesse (1988) described the hyperarousal state in panic as the "fight or flight" reaction first described by Walter Cannon in 1927 (Kaplan et al., 1994). Aggression (the "fight" response), as well as escape (the "flight" response), are viewed as the behavioral responses to a perceived threat. Even Sigmund Freud emphasized the correlation between anxiety disorders and aggression. Thus, a careful eye must be kept on patients who suffer from panic disorder, because the increased inclinations toward aggression enhance the risk of suicide as a means of easing the pain.

A study by Korn and colleagues (1997) examined the relationship between aggressive behavior and suicide attempts in 19 patients with pure panic disorder and 28 patients with comorbid panic disorder and major depression. The researchers were seeking to add definition to the exact temporal relationship between suicidal symptoms and panic symptoms.

Korn and colleagues found that approximately one in 10 patients with pure panic disorder reported attempting suicide during the panic state. Additionally, during panic attacks, the presence of comorbid depression resulted in a doubling of the rates of suicidal ideation, property destruction and assaults. The researchers also reported that there was a fivefold increase in the rate of homicidal ideation. Comorbidity, however, did not result in an increased rate of panic-associated suicide attempts. There were high correlations in the panic cohort between psychometric measures of impulsivity, suicide risk and violence risk, and panic-associated inwardly and outwardly directed aggression.

Korn et al. (1997) also found robust correlations between panic-associated suicide and aggression and overall measures of impulsivity. The authors suggested that the correlations were due to the fact that individuals who chronically manifest these forms of behavioral dyscontrol are most likely to exhibit such behaviors during the panic state. Disorders such as borderline personality disorder and substance abuse are frequently associated with impulsivity as well as aggressive tendencies (both inwardly and outwardly directed).

In 1993, Fava and colleagues reported on anger attacks in patients with major depression, a construct that may be related to the panic-associated aggression described in 1997 by Korn and colleagues. Fava et al. found these anger attacks were present in 44% of their depressed cohort. They characterized these attacks as sudden intense feelings of anger associated with typical panic symptoms such as tachycardia, flushing, sweating, shortness of breath and feeling out of control. Outward-directed aggression during anger attacks was high; 93% of the sample felt like attacking others, 63% attacked others physically or verbally, and 30% destroyed objects. Anxiety symptoms were also high, with 64% reporting symptoms of fear, panic or anxiety.

Because panic disorder is so often associated with major depression, these aggression-related findings by Fava and colleagues can support the notion that patients who suffer from panic disorder and depression are likely to experience feelings of aggression. These feelings may turn inward, which is yet another example why these patients must be carefully monitored for suicide risk.

Treatments

Given that depression frequently occurs as a comorbid condition with panic disorder, the use of antidepressants is a logical choice. Among the antidepressants, monoamine oxidase inhibitors are little used in panic disorder, mainly because of their potential for precipitating hypertensive crises if tyramine is ingested. They also have a delayed onset and can cause insomnia and orthostatic hypotension (Wolfe and Maser, 1994).

Tricyclic antidepressants (TCAs) are widely used and are effective. Their disadvantages include an association with initial activation or jitteriness, a four- to six-week time lag before onset of beneficial effect, anticholinergic effects and other troublesome side effects in a high proportion of patients, particularly during long-term use (Westenberg, 1996; Wolfe and Maser, 1994). Additionally, Westenberg (1996) pointed out, "TCAs are also cardiotoxic in overdosage, and panic disorder patients with comorbid depression are at high risk of attempted suicide."

Serotonin dysregulation has been implicated in the pathogenesis of anxiety disorders in general and panic disorder in particular. Among the TCAs, those with an effect on serotonin reuptake are most effective in panic disorder. Selective serotonin reuptake inhibitors are specifically active on serotonin reuptake and do not have anticholinergic effects nor act on the noradrenergic system. There is a clear pharmacological rationale for believing that SSRIs should be as effective as TCAs in panic disorder and should be better tolerated (Westenberg, 1996).

SSRIs have specific antidepressant and anxiolytic properties that are sustained over time and are quite likely to contribute to the healing of panic disorder. They provide improved clinical outcomes not only by reducing the frequency of panic attacks but also by improving overall anxiety, depression, phobic symptoms and measures of social impairment (Korn et al., 1997).

Fluoxetine (Prozac) is being used as an effective treatment for panic disorder with comorbid depression. In a 1998 study (Michelson et al., 1998), 243 patients diagnosed with panic disorder were treated with 10 mg/day or 20 mg/day of fluoxetine or placebo. Treatment with 10 mg/day of fluoxetine was associated "with statistically significantly greater reductions in total number of panic attacks than was placebo."

Additionally, "20 mg/day of fluoxetine, particularly, was associated with a statistically significantly greater improvement than placebo in a wide range of symptoms, including anxiety, phobia and depression." This positive response was measured by the improvement reflected on the Clinical Global Impression (CGI) scale and in disease-associated functional impairment.

Both dosages were well-tolerated by the study patients and had discontinuation rates similar to placebo. The authors noted, "Correlations between overall improvement and individual symptoms suggested that for all treatments, change in panic attack frequency was less important than changes in other symptom domains as a determinant of recovery."

One obstacle in the measurement of efficacy of a particular treatment is that panic attacks are very difficult to measure accurately. There are no truly effective methods of recording and monitoring panic attacks. Diaries can be unreliable, and patient recall may be incorrect. Patients often do not or cannot differentiate between full and limited symptoms, and these inconsistencies can affect the treating physician's idea of how effective a particular medication may be.

In another trial of fluoxetine as a means of controlling panic disorder and major depression (Louie et al., 1993), it was demonstrated that 20 mg/day may be too high a dosage for some patients. In a sample of 133 outpatients, 27 (20%) suffered from panic disorder. Of these panic disorder patients, 16 (59%) were also taking alprazolam, clonazepam (Klonopin) or lorazepam (Ativan) at stable doses for at least four weeks prior to the study and were maintained on this treatment throughout.

All patients commenced the study by taking 5 mg/day of fluoxetine, which was then increased as tolerated. Of the patients who suffered from both major depression and panic disorder, 13 were able to reach the full dose of 20 mg/day without any adverse effects. Of the lower-dose group (less than 20 mg/day of fluoxetine), nine patients with panic disorder and major depression had to discontinue fluoxetine because of adverse effects while five patients continued the lower-dose treatment. Adverse effects included anxiety, headache, sedation and insomnia. In one case, the dosage resulted in an increase in panic attacks.

When examining the low-dose patients, the presence or absence of concurrent benzodiazepine treatment did not influence the likelihood of patients being in the full-dose group, the low-dose group who discontinued fluoxetine or the low-dose group who continued fluoxetine.

When comparing patients suffering from major depression without comorbid panic disorder to those experiencing panic disorder, it was found that those suffering from depression alone had a higher tolerance for the 20 mg/day treatment of fluoxetine. Still, of the 27 patients with panic disorder and major depression, 13 (48%) tolerated the full 20 mg/day dose without any problems requiring a change or discontinuation of dosage. It is not apparent what factors caused this discrepancy, but the authors suggested that perhaps the "pretreatment state of the serotonergic system differed in the two groups and accounted for the variability in fluoxetine sensitivity."

Two SSRIs, sertraline (Zoloft) and paroxetine (Paxil), have been approved by the U.S. Food and Drug Administration for treatment of panic disorder. In a double-blind, parallel-group study by Pohl et al. (1998), 168 outpatients with panic disorder according to DSM-III-R criteria were randomized to receive either placebo or sertraline (25 mg/day for one week then flexible titration to between 50 mg/day and 200 mg/day). Among patients who completed the study, the mean number of panic attacks per week dropped by 88% in the sertraline-treated patients and 53% in the placebo-treated patients.

In a 12-week, fixed-dose study of three different sertraline dosage strengths (50 mg/day, 100 mg/day and 200 mg/day), all three doses were shown to be significantly superior to placebo in reducing the mean number of panic attacks per week (Londborg et al., 1998). The study evaluated 178 outpatients with panic disorder and was conducted at seven treatment sites. It showed that there were no significant differences in efficacy between the three dosage groups.

The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in three, 10- to 12-week, multicenter, placebo-controlled studies of adult outpatients (Physicians' Desk Reference, 2000). Patients in all studies had panic disorder with or without agoraphobia as determined by DSM-III-R criteria. Paroxetine "was shown to be significantly more effective than placebo in treating panic disorder by at least two out of three measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score."

Other SSRIs also have been investigated for efficacy in treating panic disorder. In a study by Black et al. (1993), fluvoxamine (Luvox) was compared against cognitive therapy and placebo. Seventy-five outpatients with moderate to severe panic disorder were randomly assigned to receive eight weeks of fluvoxamine, cognitive therapy or placebo. Fifty-five patients completed the treatment protocol. The Clinical Anxiety Scale (CAS) and CGI were used as clinical measures of anxiety. Ratings for the CAS and CGI showed significantly greater improvement with fluvoxamine than either cognitive therapy or placebo by completer and end-point analysis at week 8.

Another report of fluvoxamine, however, presented evidence for the emergence of moderate to severe depressive symptoms during treatment for some panic disorder patients (Fux et al., 1993). Of 230 patients treated for panic disorder and agoraphobia, 80 were treated with fluvoxamine. Seven of those 80 patients (8.8%) developed depression despite a good antianxiety response.

Two received fluvoxamine as a first-choice treatment and five as a second-choice treatment after TCAs. After this surprising development of depression, fluvoxamine was discontinued. A TCA or clonazepam (Klonopin) was administered, and the depressive symptoms eased. Five of those seven patients received fluoxetine as an alternative treatment, and all five then developed depressive symptoms.

The mean dose of fluvoxamine at the onset of depression was 100 mg/day, and the mean dose of fluoxetine was 20 mg/day. The depressive symptoms did not improve (and in four cases worsened) after the dose of fluvoxamine was increased to a mean dose of 183 mg/day and fluoxetine to a mean dose of 40 mg/day. In all of these cases, the 5-hydroxytryptophan reuptake inhibitors had a good anti-anxiety effect, and investigators found no relationship between these effects and the occurrence of depressive symptoms. These results suggest a vulnerability among some panic disorder patients to noradrenergic-serotonergic imbalance caused by SSRIs, which has to be taken into consideration.

Conclusion

Suicide presents a major challenge to the health care community. Only through recognizing the risk and developing appropriate treatments will we be able to conquer this lethal consequences of depression.

The treatment of depression alone is a challenge. When it is compounded by the anxiety that accompanies panic disorder, the patient and physician have a delicate situation on their hands. Only through the proper recognition of symptoms and risk factors can physicians correctly diagnose and treat their patients.

Keeping this in mind, emergency room physicians ought to be knowledgeable in the symptoms of panic disorder when patients present with claims of tightness in the chest, numbness, nervousness, a smothering feeling or dizziness. Once cardiac complications are ruled out, the physician ought to recommend a psychiatric evaluation to determine whether a patient is suffering from panic disorder.

Antianxiety treatment can ease the symptoms of panic disorder, and the relief will most likely prevent the patient from slipping into a major depression. The ripple effect is clear in this scenario, because preventing major depression will also prevent suicidal ideation. Thus, lives will be preserved. Through proper treatment and therapy, the anxious patient can resume a normal lifestyle without the hindrances that may otherwise impede daily activities.

It is also necessary to be aware of possible substance abuse in the patient who suffers from panic disorder. Many patients may drink alcohol to loosen anxious inhibitions. This can lead to dependence, based on the severity of the panic disorder, the genetic makeup of the patient, and the amount and frequency of alcohol ingested. Alcoholism can lead to depression in some patients and, again, we see a possible suicide risk.

It is of the utmost importance that a physician treating a patient for panic disorder examine the patient for signs of depression. This is the most likely scenario when suicidal ideations may be present. Effective management of the suicide risk lies in its accurate and timely identification, so that appropriate intervention may be commenced.

Once identified, as Fawcett (1988) comments, short-term risk factors such as anxiety and panic attacks should be viewed not merely as predictors of suicide but also as targets for intervention through the appropriate therapeutic methods. These include pharmacological intervention, most likely carefully monitored treatment with SSRIs or TCAs, ego-supportive therapy and environmental manipulation (Fawcett, 1988). Gathering a family history from panic disorder patients in conjunction with questioning them about their substance use and depressive feelings can help a physician prevent an unnecessary tragedy.

References

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We are not alone .........We are not at fault . . . Early intervention is important.