ANÁLISIS Y DISCUSIÓN DE RESULTADOS

Short and Long-term Outcomes

After DSM-III reclassification of anxiety disorders, several reports focused on the long-term outcome of panic disorder. Retrospective descriptions by individuals seen in clinical settings suggest that the usual course of the illness is generally chronic, with waxing and waning. Some individuals may have episodic outbreaks with years of remission in between, and others may have continuous severe symptomatology.

Specific follow-up studies confirm the general chronicity of PD, although with a variety of possible outcomes. Although the earliest studies, which included relatively brief follow-up periods, showed a relatively good prognosis, with recovery rates ranging from 25% to 72% after 1 or 2 years (Gloger et al., 1981; Faravelli and Albanesi, 1987; Maier and Buller, 1988), further studies reported less favourable outcomes (Coryell et al., 1983; Nagy et al., 1989; Noyes et al., 1990; Faravelli et al., 1995). After five years of prospective follow-up, only 10–12% of patients fully recovered (i.e. no symptoms and no treatment). Moreover, higher risks of suicide, major depressive episodes, cardiovascular diseases, as well as an increased general morbidity and mortality, have been reported in these patients (Coryell et al., 1988;

Weissman et al., 1989; Le´pine et al., 1993). However, since PD is frequently comorbid with other axis I and II disorders, the long-term consequences could be attributed to the comorbid condition rather than to PD itself. Recent studies seem to confirm this position: the worst consequences in terms of fatality, morbidity, and substance abuse seem to be related to the associated conditions (Wittchen and Essau, 1989; Johnson et al., 1990; Le´pine et al., 1993).

Noyes et al. (1990) found that patients with extensive phobic avoidance or agora-phobia have a more severe form of PD, with a longer duration of illness, more severe symptoms and greater social maladjustment than subjects with limited or no phobic avoidance. Breier et al., Lesser et al. and Noyes et al. found that subjects with panic disorder with secondary depression (current or past) were part of a more severely ill group: they had been ill longer and had more severe anxiety symptoms, more frequent panic attacks and more extensive phobic avoidance, and they more fre-quently had personality disorders (Breier et al., 1984; Lesser et al., 1988; Noyes et al., 1990). There is some evidence that concomitant personality disorders influence the outcome of patients with PD: the presence of a personality disturbance predicts in fact a less favourable treatment response (Reich et al., 1987; Roy-Byrne et al., 1988;

Noyes et al., 1990). When PD is the primary psychopathological condition, the rate of recovery is relatively low (12%) and that PD tends to be chronic disturbance (Faravelli

relationship to outcome: patients with a shorter duration of illness more frequently experienced a complete recovery or remission and reported fewer relapses. In this sample, the number of suicides is small.

Using data from the ECA study, Markowitz et al. (1989) reported that PD (with or without agoraphobia) was associated with a greater risk of poor physical and emo-tional health, alcohol and other drug abuse, suicide attempts, poorer marital func-tioning, and greaterfinancial dependence. The risk for PD was even greater than for major depression for many measures, including alcohol abuse andfinancial depend-ence. ECA suicide rates for the separate diagnoses of panic disorder or major depression alone were similar and were higher than rates for the general population.

Patients with PD had levels of mental health and role functioning that were substan-tially lower than those of patients with other major chronic medical illnesses (Sher-bourne et al., 1996). PD is associated with poor quality of life (Katerndahl and Realini, 1997): comorbid depression, social support, worry and severity of chest pain predicted quality of life. Although subjects with infrequent panic attacks reported a lower quality of life than controls, subjects with PD had more panic-related disability and poorer quality of life than those with infrequent panic attacks. Predictors of work disability included panic frequency, illness attitudes and family dissatisfaction.

Coryell (1988) reviewed earlier studies from 1936 to 1986 and concluded that patients with anxiety states appeared as likely as patients with primary depression to commit suicide. Weissman et al. (1989) found a very high rate of suicide attempt and suicidal ideation in subjects suffering from PD even when controlling for lifetime major depressive episode and alcoholism. Le´pine et al. (1993) found that 42% of outpatients with PD had attempted suicide at some time during their lives. In patients with PD, they found demographic determinants for suicide attempts to be similar to those of other clinical populations, such as depressed patients: the suicide attempts occur most frequently in single, divorced, or widowed women. In this study the authors found a significantly longer duration of panic disorder at the time at referral in suicide attempters. Otherwise, severity of the worst episode of PD did not differ between suicide attempters and non-attempters. They found that suicide attempt in patients with PD were often associated with a lifetime diagnosis of major depressive episode and alcohol and/or other substance abuse. Warshaw et al. (1995) found that suicidal behaviour in subjects with PD seems to be better related to factors not inherent in the PD; presence of depression, post-traumatic stress disorder, eating disorders, substance abuse/dependency or personality disorders (in particular, bor-derline and antisocial personality disorders) and factors related to quality of life (in fact, being married or having a child, working full-time all seemed to be protective factors).

lifetime rates, the odds ratios for comorbidity of PD with agoraphobia range from 7.5 in the ECA to 21.4 in Puerto Rico, and those of PD with major depression range from 3.8 in Savigny to 20.1 in Edmonton (Weissman et al., 1997). In the NCS the odds ratio is 10.6 for agoraphobia and 5.7 for major depression. The presence of agora-phobia with PD represents more severe disturbance and involves a higher likelihood of one or more comorbid diagnoses.

Goisman et al. (1995) found lifetime panic with and without agoraphobia to co-exist with at least one other anxiety disorder 37% of the time. Klerman et al.

(1991) found 33% of 254 subjects with PD to have comorbid agoraphobia and 72% of these 254 to have comorbid agoraphobia, major depression, alcohol abuse, or drug abuse. Johnson et al. (1990) found more than two-thirds of ECA subjects with lifetime PD to meet criteria for more than one of 10 other axis I diagnoses. Cassano et al.

(1999) found 70% of 302 patients with current DSM-III-R panic disorder to also have at least one of seven additional current syndromes of which the most common is GAD. Uncomplicated panic is most likely to exist independently, but even this disorder is found alone in less than 50% of the time (Goisman et al., 1995): GAD and social phobia were the most frequent comorbid diagnosis. Panic with agoraphobia is seen as a sole diagnosis on 40% lifetime. The comorbid diagnoses at similar rates (about 20%) are simple and social phobia and GAD. Joyce et al. (1989) found lifetime DSM-III GAD to be more frequent in subjects with a history of panic attacks with

‘‘moderate phobic avoidance’’ than in those with a history of panic attacks alone.

Subjects with agoraphobia without a history of PD have at least two additional diagnoses at almost twice the frequency of subjects with uncomplicated PD and GAD was the disorder most frequently comorbid, followed by social phobia and simple phobia; 32% of subjects had agoraphobia without a history of PD as the sole diagnosis (Goisman et al., 1995).

A possible explanation of high comorbidity between anxiety disorders is that these disorders may share some common aetiologic pathways. Barlow (1988) notes that the experience of some symptoms of anxiety may lead to an anticipation of more anxiety:

this anticipation, in fact, is itself anxiety-provoking, leading to ever-increasing expec-tation, pattern recognition, and further expectation. If this is the case, then it is likely that having one anxiety diagnosis should decrease the threshold for having a second.

The studies indicate that this second diagnosis is often GAD (Goisman et al., 1995;

Noyes et al., 1992): this argument could lead to a call to abolish GAD as a separate entity and regard it only as a somewhat inevitable non-specific by-product of having any of a number of chronic anxiety disorders. In addition, PD appears to be more likely to be preceded by another psychiatric disorder than to be a chronologically primary condition. Apart from the affective disorders, there are relatively few other psychiatric conditions appearing after the onset of PD. Thisfinding implies that some primary disorders (e.g., simple phobia, social phobia, substance abuse) may represent a specific predisposition for the development of PD.

There are reports that 35% to 91% of patients with panic disorder also suffer from

degree of overlap in the transmission of these disorders occurs as well (Merikangas et al., 1990; Weissman, 1990): these data are inconclusive as to whether one condition predisposes another or whether there is common aetiology. Leckman et al. (1983) found thatfirst-degree relatives of patients dually diagnosed with major depression and PD have markedly increased morbidity risk for depression, panic, phobias and alcoholism. In many cases, both disorders occur at the same time (Vollrath et al., 1990). In others PD occurs before the onset of depressive disorder as well as before the onset of substance abuse (Wittchen, 1988).

Breier et al. (1984) found that patients with PD and/or agoraphobia who had a current or past major depressive episode had more severe symptoms of both anxiety and depression than those who had never been depressed. In a naturalistic study, Van Valkenburg et al. (1984) reported that patients with secondary depression had an earlier age at onset of their PD but did not differ from non-depressed patients with PD in their treatment response or psychosocial outcome. While it might be reasonable to expect that patients with depression would have suffered from PD longer than those without depression, patients with and without histories of depression have had PD for similar lengths of time (Starcevic et al., 1993). Also, while it is conceivable that patients with more severe agoraphobic avoidance would be more likely to experience depression than patients with less severe avoidance, this is not supported by empirical evidence. Thus, there is little support for the hypothesis that the depression, which frequently complicates PD, is aetiologically secondary to the long-term demoralising effects of chronic agoraphobic avoidance.

The co-existence of social phobia and PD is far from rare. The patients comorbid with social phobia and PD have an earlier PD age of onset; have more obsessive compulsive disorders and more severity in the social phobia scale from the Fear Questionnaire of Marks and Mathews (Segui et al., 1995). While neither duration of PD nor agoraphobic severity was related to a history of major depression, the concomitant diagnosis of social phobia was associated with significantly greater lifetime risk for depression. The data, however, should not be used to support a casual relationship. It is possible that in making concomitant diagnoses of social phobia, we are identifying a subgroup of PD patients with a constellation of personality traits that includes low self-esteem, extreme self-consciousness, and a tendency towards nega-tive self-appraisal. Such a subgroup could be at considerable risk from depression based on psychological, particularly cognitive, factors. Additionally, the social isola-tion experienced because of social avoidance could contribute to a propensity for becoming depressed. Alternatively, concomitant social phobia may merely be a marker for a more severe illness.

Since the co-occurrence of significant obsessive-compulsive symptoms has also been noted to increase the lifetime risk for depression in patients with PD, it is possible that PG complicated by the presence of any other disorder, rather than social phobia specifically, may increase the risk for depression.

Another risk factor in PD is the development of alcohol abuse, which some view as

Noyes et al., 1986) suggest that PD has a higher than expected prevalence among alcoholics compared with the prevalence in the general population. The question concerning primary and causal relationship between the two disorders, i.e. whether alcoholism leads to the development of anxiety disorders or vice versa, is less clear.

George et al. (1990) suggest that a possible mechanism for the link between alcohol-ism and anxiety is a kindling process: the hyper-responsive CNS state that results from repeated alcohol withdrawal may, in susceptible individuals, give rise to a heightened state of anxiety and panic attacks even during sobriety. The model of kindling process has been proposed by Ballanger and Post. They demonstrated that the alcohol withdrawal syndrome becomes progressively more severe with increasing years of heavy daily alcohol abuse, irrespective of age. They propose that repeated episodes of withdrawal in chronic alcoholics serve as stimuli for kindling of subcortical structures, primarily limbic, hypothalamic, and thalamic nuclei. They hypothesise that the spectrum of withdrawal symptoms from mild withdrawal with tremor and autonomic symptoms to the more severe withdrawal symptoms of hallucinations, psychic symptoms, epileptic seizures, and delirium tremens are secondary to cumu-lative physiological changes which accompany a kindling-like process (Ballanger and Post, 1978). Malcolm et al. (1989), in a double-blind controlled study, found that carbamazepine, because of its ability both to retard the development of kindling and suppress established kindled foci, is as effective and safe as benzodiazepine treatment for alcohol withdrawal.

Marazziti et al. (1995) found that current anxiety disorders, especially panic and related conditions, are the most common psychiatric disorders associated with head-ache. Thesefindings were particularly true of the subgroup of migraine with aura; in the relatively few patients with mood disorders, depression was nearly always comorbid PD and past history of depression was mainly a characteristic of the tension headache group. These data are compatible with the hypothesis that migraine, especially that with aura, PD and some forms of depressive illness are part of the same spectrum.

Irritable bowel syndrome (IBS) is fairly common in patients seeking treatment for PD: in Kaplan’s study 46.3% patients with PD met the criteria for IBS (Kaplan et al., 1996). Patients with PD and IBS were more likely to report symptoms of back pain as well as personal history of bowel disease compared with patients with panic disorder but without IBS.

Otoneurological abnormalities have been reported in PD; vestibular abnormalities are most prevalent in the patients with PD with moderate to severe agoraphobia (Jacob et al., 1996). Vestibular dysfunction was associated with space and motion discomfort and with frequency of vestibular symptoms between, but not during, panic attacks. The constellation of vestibular test most specific for agoraphobia was one indicating compensated peripheral vestibular dysfunction. Therefore a subclini-cal vestibular dysfunction may contribute to the phenomenology of PD, particularly in the development of agoraphobia in panic disorder.

in the severity of pulmonary function abnormalities or in the response to bronchodi-lators. However, patients with panic attacks were significantly more likely to report dyspnea at rest and irritable bowel symptoms and tended to report difficulty swallow-ing.

Bouwer and Stein (1997) found a specific association between PD and a history of traumatic suffocation which is significantly more frequent among the PD patients than among the comparison subjects. Within the PD group, patients with a history of traumatic suffocation were significantly more likely to exhibit predominantly respir-atory symptoms and nocturnal panic attacks, while patients without such a history were significantly more likely to have predominantly cardiovascular symptoms, oculovestibular symptoms and agoraphobia.

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