ISSUES IN THE MANAGEMENT OF DIFFICULT PANIC PATIENTS

 Dr. Suresh Kumar. MD, DPM, DNB (Psych), MNAMS Senior Lecturer, Department of Psychiatry, Medical College, Calicut, Kerala
 Panic disorder with or without agoraphobia is a common, debilitating psychiatric condition that will affect 1.5-2.5% of the general population at sometime in their lives (Pelissolo & Lepine 1988). Since its introduction in DSM lll (Diagnostic and statistical Manual of Mental disorder) in 1980 lot of research have been done in panic disorder which has enabled the management of this disorder. However the most difficult problem faced by the clinician today is choosing the most appropriate treatment or who creates some particularly difficult clinical problem
Diagnosis, differential diagnosis and comorbidity
 Panic disorder is characterized by spontaneous, unexpected and recurrent panic attacks that are short lived (usually less than one hour) with intense fear, anxiety or discomfort. They are followed by at least one month of persist and fear of having other panic attacks (anticipatory anxiety) worry about the possible implications or consequences, or a significant behavioural change related to the attacks. Panic attacks secondary to effects of a substance or a general medical condition is an exclusion criteria in the diagnosis. The diagnostic criteria for a panic attacks is listed in table 1.
 Table 1
Diagnostic Criteria for Panic Attack
 A discrete fear or discomfort in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes.
 - Palpitations, pounding heart or accelerated heart rate
 - Sweating
 - Trembling or shaking
 - Sensations of shortness of breath or smothering
 - Feeling of choking
 - Chest pain or discomfort
 - Nausea or abdominal distress
 - Feeling dizzy, unsteady, light-headed or faint
 - Derealisation (feeling of unreality) or depersonalization (being detached from oneself)
 - Fear of losing control or going crazy 
 - Fear of dying
 - Paraesthesias (numbness or tingling sensations)
 - Chills or hot flushes
Source - American Psychiatry Association (1994)
 Two forms of panic disorder are codified in DSMIV with or without agoraphobia. Patients with agoraphobia avoids situations or places in which escape might be difficult or help may not be available in the event of a panic attack. The degree of phobic avoidance may be considerable, restricting the patient housebound with the need for some agoraphobics to be accompanied by somebody always.  
 Even if the diagnosis of panic disorder with or without agoraphobia is relatively clear in most cases, the differential diagnosis of this condition includes a large number of general medical conditions and psychiatric disorders (Kaplan & Sadok, 1994). Medical differential diagnosis includes cardiovascular diseases (angina, Hypertension, paradoxical atrial Tachycardia, Mitral valve prolapse) Pulmonary diseases (asthma), neurological diseases (epilepsy, Migraine, Menieres diseases), endocrine diseases, (hyperthyroidism, pheochromocytoma, hypoglycemia) and drug intoxication on withdrawal. Concerning psychiatric disorders, the clinician has to determine whether panic attacks are situationally bound or predispose (phobias, obsessive compulsive disorder or depressive disorder) However, difficult panic patients may have comorbid disorders such as social phobia, alcohol or substance abuse, personality disorders and depression. Other psychiatric differential diagnose include post traumatic stress disorder, depersonalization disorders and somatoform disorder. The severity of panic disorder is related to the intensity and frequency of panic attacks, degree of intrusiveness of anticipatory anxiety and the impairment associated with avoidance behaviour.
 Pharmacotherapy panic disorder (table 2)
 Tricyclic Antidepressants
 The earliest reports on the antipanic properties of TCA appeared in 1960s especially with Klein's studies using imipramine (Klein, 1964). Imiparamine and clomipramine has been the most extensively studied in this class of medication with demonstrble antipanic efficacy. Effective dose of imipramine ranges between 150-250 mg/day and clomipramine in a lower dose range (75-150 mg/day). Other tricyclics with some evidence of efficacy include desimipramine, doxepine, amitrptyline, and nortriptyline.
 Table - 2
 Drug treatment for panic disorder
 Effective treatments 
  •  SSRIs :
 Fluvoxamine (150-300 mg/d)
 Paroxetine (40-60 mg/d)
 Sertraline (50-200 mg/d)
 Citalopram (20-30 mg/d)
 Fluoxetine (20-60 mg/d)
  •  Tricyclic antidepressants :
 Clomipramine (75-150 mg/d)
 Imipramine (15-250 mg/d)
  •  High potency benzodiazepines:
 Alprozepam (4-6 mg/d)
 Clonazepam (2-3 mg/d)
  •  MAOI 
 Phenelzine (45-90 mg/d)
 Management
  •  Very slow increase of the dose at the beginning
  •  Dosage adjustment according to side-effects and outcome 
  • Acute phase: 6-8 weeks
  •  Continuation phase: 6-12 months
  • Long term treatment: 2 years or more
  • Slow tapering with a close supervision at the end
 Source : Pelissolo & Lepine (1999)
 The advantage of these medication are:
 The advantage of these medications are:
 - Once day dosing 
 - No benzodiazepine type of physiological dependence or withdrawal 
 - No dietary restrictions like MAOI.
 Disadvantages
 Anticolinergic effects, orthostatic hypotention, weight gain all these may lead to non compliance with consequent emergence of panic attacks.
 Interestingly, agoraphobic patients may require higher doses of clompramine or imipramine than depressed patients (Ballenger, 1998).
 MAOI
 The classical irreversible MAOI are effective in treating panic disorder with anecdotal observations suggesting that they are more effective than imipramine. Among these phenelzine is the most powerful antipanic (Modigh et al, 1992). RIMAs are somewhat less effective than irreversible MAOIs
 Advantages 
 - Less tendency to cause activation
 - No tolerance / dependence
 - Lower anticholinergic side effects 
 Disadvantages
 - Orthostatic hypotention
 - Weight gain
 - Sexual dysfunction
 - Dietary restriction (low thyramine diet)
 - Potential for tyrramine induced hypertensive crised.
 SSRI
 Most clinicians consider SSRI the first line drug for the management of panic disorder. They are also useful for panic disorder patients with comorbid conditions including depression, social anxiety disorder, or obsessive compulsive disorder (Bellenger et al 1998). Fluoxamine was the first SSRI evaluated in a double blind study in panic disorder. In a dose range of 150-300 mg/day, patients reported considerable improvement than placebo (denBoer & Westenberg,1990). Though there are no published double blind placebo controlled studies, few studies have reported the efficacy of fluoxetine in a dose range of 20-60 mg/day. It success rate appears to be higher with longer duration treatment and with higher doses. However, higher drop out rate, paradoxical anxiety and activation are reported during early phase of treatment (Pecknold et al, 1995)
 Sertraline
Sertraline was approved by U.S. Food and Drug administration in 1997 for use in panic disorder. For the maximum benefit the dose should be gradually increased to greater than 125 mg/day for an average patient (Shechan)
 Paroxetine
 This is the first SSRI to receive FDA approval for use in panic disorder and it is the most well studied SSRI in the management of panic disorder (Boer, 1998) the usual dose range is 40-60mg/day with a more rapid onset of  action. The efficacy of citaloparm, venlafaxine, nefazodone also has been evaluated with panic disorder with encouraging results (Sheehan, 1999).
 The disadvantage of SSRI is a paradoxical worsening of anxiety on initiation of treatment which can be reduced why concomitant of benzoiazepine which act synergically to block the anxiogenic effect of SSRIs thereby lead  to better tolerability as well as help to attain therapeutic dosing level of SSRI 
 Benzodiazepines (alprazolam, clonazepam, adinazolam)
 High potency BZDs constitute another class of drugs with a demonstrated efficacy in panic disorder. The primary advantage of BZD is rapid relief from anxiety and panic attacks. The disadvantages include sedation, cognitive clouding, interaction with alcohol, dependence and withdrawal syndrome (Salzman, 1993)
 Combination Therapy (table 3)
 If no improvement is acheived with the maximum tolerated dose of adequete duration, the second line recommendation is to switch medication to one of another class i.e. an SSRI, TCA or high potency BDZ. Another choice in case of partial response is a combination of existing drug with an add on TCA/SSRI or high potency BDZ (Stabl, 1998). If the first drug used is an SSRI on consensus group had suggested trying another SSRI if there were  no tolerance problems and some indication of partial response (Ballenger et al, 1998). 
 When several first or second line treatments are not fully effective MAOI may be considered especially phenelzine or tranycypromine (Lepine et al, 1997). One of there advantages is a better antiphobic action though their use is restricted because of distinct side effect profile.
 Other alternative propositions based on case reports or open study findings are use of buspirone, nefazodone, alproate, carbamazepine verapamil, baclofen, ondansetron and inositol either in monotherapy or in various combinations (Pelissolo & Lepine, 1999). Their use may be justified only in multidrug resistant patients.
Table 3 : Combination therapy for panic disorder
TCA + BZ
MAOI + BZ
SSRI + BZ + CBT
SSRI+BZ+Buspirone/fenfluramine/ tradazone/nefazodon
The basis of many combination therapy is high potency benzodiazepin. Added to this basis may be any number of antidepressants such as TCA combo, MAOI combo, an SSRI combo or possibly an SSRI plus the same serotonin boosters used in combination therapy for depression and for ODC. CBT can also be added to any of the these drug treatments.
Duration of treatment and long term pharmocotherapy
 Natural history of panic disorder is chronic with  remissions and relapses. However there are no data on the optimal duration of treatment. From a clinic point of view, length of treatment depends on severity of panic disorder and agoraphobia. For mild disorder or illness of less than 6 months duration, 6 months treatment may be appropriate. Severe and persistent panic disorder need at least 12 months treatment at probably up to 2 years. In all cases, discontinuation of medication can only be considered when full, sustained remission is achieved, anxiety management skills are achieved, and when patients have a stable life situation. The drug must be tapered slowly over a period of 2-6 months with close supervision because of the risk of rebound and relapse (Ballenger et al, 1998).
 Most controlled studies on the pharmacotherapy of panic disorder have been short term studies, but long term efficacy data are available for TCAs, paroxetine and aiprazolam for about 9 months maintenance treatment (den Boer, 1998). Further, some data indicates that improvement will continue with the prolonged administration of antipanic agents (Londborg et al, 1998) No loss of efficacy is reported when lowering the dose during maintenance phase (Noyes & Perry, 1990).
Psychological treatment (Pelissolo & Lepine, 1999)
 Cognitive and behaviour therapy are commonly combined in the psychological treatment of panic disorder with or without agoraphobia. Cognitive therapy focuses on identifying the cognitive disortions and modifying them, where as behaviour therapy attempts to modify patients responses often through explosure to situations or physiological stimuli that are associated with panic disorder. Behavior therapy is the most effective in treating phobic avoidance and the improvement will last longer than the drug treatment.  
 The ingredients of cognitive behaviour therapy for panic disorder are as follows:
- Detailed behaviour analysis of panic attacks, anxiety, positive and negative reinforcements, agoraphobia behaviours and comorbid affective or anxiety disorders.
- Self monitoring techniques of keeping a daily record of panic attacks and their limitation in certain activities. This will help to get a baseline assessment of illness severite as well as progress of improvement. 
- Relaxation techniques like respiratory control with diaphramatic breathing to control hyperventilation, progressive muscular relaxation and cue-controlled relaxation will help to apply their relaxation skills in daily life (such as attending a meeting or when traveling by train) and in fear provoking situation. This is known as applied relaxation.  
- Graded exposure techniques with gradual desensitization to external stimuli till extinction of the anxious response is attained. 
- Exposure to anxiogenic internal sensation such as hyperventilation with breathing retraining.
- Cognitive restructuration with special attention focused on catastrophic misinterpretation of bodily and mental experiences. 
Other forms of psychosoical treatments 
 Addressing  the agoraphobic's interpersonal system, in combination with exposure treatment, can be useful particularly with difficult, can be useful particularly  with difficult patients (Chambless & Gillis, 1994). using spouse as co-therapist in educational and treatment interventions may help agoraphobic patient to carry out homework exercises (Cobb et al, 1994). Some forms of marital therapy such as couples communication and problem solving training in addition to exposure therapy may have positive effects on outcome (Arnow et al, 1985).
 Combined drug and psychological treatments (Noyes et al 1993)
 Fore severe forms of illness or for resistant patients a combination of psychological and pharmacological treatment is clearly necessary. Tailoring treatment programs to the individual patient is becoming the state of the art, although such combinations are generally inadequately investigated in controlled trails. quite often patients who are so anxious or depressed initially to participate in psychotherapy may be excluded from such sessions until they improve with medication. Some feel that BDZ interfere significantly with CBT as certain amount of anxiety must be present for CBT to be effective.
 Social recommendation for the management of difficult patients
 Even if majority of panic patients can be improved adequately with drug and/or psychological treatments, a significant number will be partial or complete non-responders to first line treatment. For e.g. 30-40 % of patients fail to benefit completely from exposure therapy, 65%have partial recovery and may continue to seek pharmacological of psychological help after exposure therapy (Chambless & Gillis, 1994). Noyes et al (1993) in a 7 year follow up study have pointed out several predictors of poor outcome namely severe panic and agoraphobic symptoms, hospitalization, longer duration of illness, comorbid depression, high personality sensitivity and a number of significant life events or environmental factors such as separation from a parent by death of divorce, low social class and unmarried status. It is important to recognize these poor outcome factors early in the cours of treatment so that suitable interventions can be applied. 
 Educating the patient about the symptomatology, course and treatment will improve patient's comprehension about their sensations or behaviours reduce demoralization and improve doctor-patient relationship. Giving the patient the right to chose between various therapeutic strategies will make the patient more active and improve compliance. Management of medication side effects will also affect successful outcome by preventing rebound subsequent to drug stoppage. A possible residual symptomatology in the form of a limited panic attacks, minor phobic avoidance of anticipatory anxiety can lead to demoralizing counteractions that disrupt full compliance with the treatment and hence facilitate relapse.
 An important point is comorbidity which can after the validity of diagnosis, influence patients compliance and modify treatment efficacy. A complete psychological and medical and medical assessment is needed as 70% of panic patients may have comorbid conditions that should be considered when planning treatment (Wolf & Maser, 1994). Even with severe psychiatric comorbidity, panic attacks should be treated first because it is demoralizating to the patients. Moreover, careful assessment of substance abuse or dependence is also needed including alcohol, cannabis, opiates, coffeine, BDZ, cocaine, hallucinogens and over the counter drugs.