Panic disorder antidepressants

SSRIs are widely used for treatment of depression, as well as, for example, panic disorders and obsessive—compulsive disorder. These dmgs are well recognized as clinically effective antidepressants having an improved side-effect profile as compared to the TCAs and irreversible MAO inhibitors. Indeed, these dmgs lack the anticholinergic, cardiovascular, and sedative effects characteristic of TCAs. Their main adverse effects include nervousness /anxiety, nausea, diarrhea or constipation, insomnia, tremor, dizziness, headache, and sexual dysfunction. The most commonly prescribed SSRIs for depression are fluoxetine (31), fluvoxamine (32), sertraline (52), citalopram (53), and paroxetine (54). SSRIs together represent about one-fifth of total worldwide antidepressant unit sales. 

Antidepressants are small heterocyclic molecules entering the circulation after oral administration and passing the blood-brain barrier to bind at numerous specific sites in the brain. They are used for treatment of depression, panic disorders, generalized anxiety disorder, social phobia, obsessive compulsive disorder, and other psychiatric disorders and nonpsychiatric states. 

An Australian study compared medical utilization and costs in patients with panic disorder, those with social anxiety disorder, and a control group (Rees et al, 1998). Almost half of the panic disorder patients had seen a primary-care physician more than seven times over a 6-month period, compared with 7% of the social phobic patients and none of the control group. The mean costs were A 150, A 60 and A 20 respectively. The patients with panic disorder were treated with antidepressants (39%), benzodiazepines (15%), relaxants (12%), beta-blockers (7%) and other medication (7%). Twenty per cent received no medication. Patients with panic... 

Panic disorder patients are more likely to experience stimulantlike side effects than patients with major depression and should be initiated on lower doses of antidepressant than those that are used for depression or other anxiety disorders. 

MAOIs are reserved for the most difficult or refractory panic disorder patients. Side effects and dietary and drug restrictions affect patient acceptance (see Chap. 70 for food and drug restrictions). Fluoxetine must be stopped 5 weeks before phenelzine (or another MAOI) is started. Other antidepressants should be stopped 2 weeks before phenelzine is started. 

BZs are second-line agents except when rapid response is essential. They should not be used as monotherapy in panic disorder patients with a history of depression or alcohol or drug abuse. BZs are often used concomitantly with antidepressants in the first weeks to offset the delay in onset of antipanic effects. 

SSRIs are initiated at doses similar to those used for depression (see Table 68-13). If there is comorbid panic disorder, the SSRI dose should be started at one-fourth to one-half the usual starting dose of antidepressants. The dose should be tapered slowly during discontinuation to decrease the risk of relapse. 

One drawback to MAOI therapy is that the therapeutic benefit typically does not begin until after the third week of treatment at the earliest. This is, of course, generally true of all antidepressants that are used to treat panic disorder and other anxiety syndromes. Of greater concern are the potentially dangerous food and drug interactions of the MAOIs (cf. Chapter 3), which have relegated the use of MAOIs for those panic disorder patients who do not respond to other treatments. 

Tricyclic Antidepressants (TCAs). The TCAs, particularly imipramine (Tofranil), were also discovered soon after their introduction to be effective in the treatment of panic attacks. Imipramine, the best-studied TCA in the treatment of panic disorder, is most often helpful at daily doses of 150-250 mg, though it must be started at 10-25 mg, usually at bedtime, and gradually increased over 2-4 weeks. Although they are not as well studied, many clinicians prefer to use the secondary amine TCAs, desipramine (Norpramin) and nortriptyline (Pamelor), because they have milder side effects than imipramine. Clomipramine (Anafranil), though probably the TCA with the greatest side effect burden, is often said to be most effective in patients with refractory disease. 

Newer Generation Antidepressants. All SSRIs have been shown effective in the treatment of panic disorder. Of these, flnoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), as well as the SNRI venlafaxine ER (Effexor XR), have received FDA approval for the treatment of panic disorder. Because they are safer and easier to tolerate, SSRls/SNRls have largely supplanted the MAOIs and TCAs as standard treatments (along with benzodiazepines) for panic disorder. 

When treating mild-to-moderate panic disorder, we recommend avoiding benzodiazepines in favor of CBT or antidepressants. Because CBT and antidepressants are both effective for panic disorder and major depression (commonly comorbid with panic disorder), the choice between the two largely rests on patient preference. Antidepressants are preferred for those who are pessimistic regarding the potential benefit of CBT, cannot afford CBT, or are unable (or unwilling) to invest the time necessary to complete a course of CBT. In our experience, some patients may accrue significant beneht from the combined treatment, particularly those with more moderate symptoms who struggle with the exposure aspects of therapy. 

We do not use benzodiazepines as readily when treating GAD as we do when treating panic disorder. In comparison to those with panic disorder, most patients with GAD can more easily tolerate the delay in treatment response and even any transient exacerbation of anxiety associated with antidepressant therapy. Benzodiazepines are reserved for those who present with especially severe anxiety that necessitates more rapid relief than an antidepressant can afford and for those who do not achieve a satisfactory response to antidepressant or buspirone therapy. Due to the persistent nature of the anxiety experienced by patients with GAD, shortacting benzodiazepines such as alprazolam are not especially helpful unless dosed 3-4 times per day. Instead, we prefer long-acting agents such as clonazepam. When used to treat GAD, clonazepam should be started at a low dose (0.25-0.5 mg/day) and titrated to higher doses (1-4 mg/day) if clinically necessary. 

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

Long-term use The effectiveness of long-term use of SSRIs for OCD, panic disorder, and bulimia has not been systematically evaluated. However, the long-term use of SSRIs for depression has been evaluated and demonstrated to maintain antidepressant response for up to 1 year. 

In recent years many of these primary care cases that would formerly have been seen as anxiety disorders have been portrayed as anxious-depressives and have led to treatment with antidepressants, in particular the more recent serotonin reuptake inhibitors. As part of this rebranding a variety of states such as panic disorder, post-traumatic stress disorder, social phobia and generalized anxiety disorder have appeared, along with more traditional disorders such as obsessive compulsive disorder (OCD). Many of these diagnoses are likely to lead to prescriptions of an SSRI although the evidence for benefit from SSRIs is poor except for OCD. 

Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA, Charney DS, Krystal JH (2001) Reductions in occipital cortex GABA levels in panic disorder detected with Ih-magnetic resonance spectroscopy. Arch Gen Psychiatry 58 556-561 Grant MM, Weiss JM (2001) Effects of chronic antidepressant drug administration electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry 49 117-129... 

Taken together, the efficacy of antidepressants covers the spectrum of anxiety disorders, although there are important differences between drugs in the group (Table 3). Several new antidepressants have been marketed since the SS-RIs venlafaxine and mirtazapine are discussed later (Sects. 3.2.1.2 and 3.2.1.4) nefazodone, a serotonin reuptake inhibitor and postsynaptic 5-HT2 blocker showed promise in early studies but was recently withdrawn by its manufacturers reboxetine, a noradrenaline reuptake inhibitor (NARI) showed benefits in panic disorder in one published study (Versiani et al. 2002) and further evidence of its anxiolytic efficacy is awaited. 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J (1995) A placebo-controlled trial of L-365,260, a CCK antagonist, in panic disorder. Biol Psychiatry 37 462-466 Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek IJ, Reines SA, Snavely D, Wyatt-Knowles E, Hayle EJ (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281 1640-1645 Kriegsfeld LJ, Dawson TM, Dawson VL, Nelson RJ, Snyder SH (1997) Aggressive behavior in male mice lacking the gene for neuronal nitric oxide synthase requires testosterone. Brain Res 769 66-70... 

Pohl, R., Yeragani, V.K., Balon, R., and Lycaki, H. (1988) The jitteriness syndrome in panic disorder patients treated with antidepressants. J Clin Psychiatry 49 100-104. 

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