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[email protected] CNS & Neurological Disorders - Drug Targets, 2014, 13, 1057-1065
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Current Pharmacological Interventions in Panic Disorder Rafael C. Freire*,1, Sergio Machado1,2, Oscar Arias-Carrión3,4 and Antonio E. Nardi1 1
Laboratory of Panic and Respiration, Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. National Institute for Translational Medicine (INCT-TM), Brazil
2
Physical Activity Neuroscience Laboratory (LABNAF), Physical Activity Sciences Postgraduate Program of Salgado de Oliveira University (PPGCAF/UNIVERSO), Niterói, Brazil
3
Trastornos del Movimiento y Sueño (TMS), Hospital General Dr. Manuel Gea González, México D.F., Mexico
4
Trastornos del Movimiento y Sueño (TMS), Hospital General Ajusco Medio, México D.F., Mexico Abstract: The aim of this review was to summarize the recent evidences regarding the pharmacological treatment of panic disorder (PD). The authors performed a review of the literature regarding the pharmacological treatment of PD since the year 2000. The research done in the last decade brought strong evidences of effectiveness for paroxetine, venlafaxine, sertraline, fluvoxamine, citalopram, fluoxetine, clonazepam, and the relatively novel agent escitalopram. There are evidences indicating that the other new compounds inositol, duloxetine, mirtazapine, milnacipran, and nefazodone have antipanic properties and may be effective compounds in the treatment of PD. The effectiveness of reboxetine and anticonvulsants is a subject of controversy. In addition to selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines and atypical antipsychotics may be valid alternatives in the treatment of PD. Recent data indicate that augmentation strategies with aripiprazole, olanzapine, pindolol or clonazepam may be effective. D-cycloserine is a promising agent in the augmentation of cognitive behavioral therapy.
Keywords: Anti-anxiety agents, antidepressive agents, antipsychotic agents, benzodiazepines, clinical trial, cognitive therapy, comparative study, panic disorder. INTRODUCTION In the general population the lifetime prevalence of panic disorder (PD) ranges from 1 to 3% and in clinical settings the prevalence ranges from 3.0 to 8.3% [1-3]. These patients have an increased risk of comorbid psychosis, manic behavior, drug abuse, depression, dysthymia, and suicide [4]. Patients with clinical and subthreshold PD show high unemployment rates, have significant work impairment, seek medical treatment more frequently and have more hospitalizations than people without panic symptoms [4]. The annual per capita costs of clinical PD with/without agoraphobia in Netherlands is 13,894 €, while the costs of subclinical PD with/without agoraphobia is 8,070 €, higher than other psychiatric disorders [5]. The longer PD patients remain untreated, the higher is the risk of increased comorbidity [6] and nonresponse to pharmacotherapy [7]. Therefore, these patients should be treated effectively with pharmacological or (cognitive) behavioral therapy as soon as the symptoms emerge [8]. Panic attacks are acute fear reactions to internal or external stimuli that occur in subjects with abnormally sensitive fear networks, such as PD patients. This fear network, centered in the central nucleus of the amygdala (CNA), also includes amygdalar projections to the brainstem *Address correspondence to this author at the Laboratory of Panic and Respiration, Federal University of Rio de Janeiro, Address: Rua Visconde de Piraja 407/702, Rio de Janeiro, Zip code: 22410-003, RJ, Brazil; Tel/Fax: 55 21 2521 6147; E-mail:
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and hypothalamus, the prefrontal cortex, insula, and thalamus. The sensory input for the conditioned fear stimulus runs through the anterior thalamus to the lateral nucleus of the amygdala, thence to the CNA, where all the information is gathered and the autonomic and behavioral responses are coordinated. A deficiency in the coordination of stimuli from the cortex and brainstem could lead to an abnormal activation of the amygdala, with behavioral, autonomic, and neuroendocrine stimulation. Studies indicate that increases in serotonergic transmission may have an inhibitory effect in the amygdala and on the fear-related structures. Some antidepressants increase noradrenergic activity and modulate the noradrenaline realeases related to stressful situations. Compounds that bind to the γ-aminobutyric-acid (GABA) receptors also have an inhibitory effect on the limbic system. These drugs probably act in the CNA and its projections by decreasing the sensitivity of the fear network and thus reducing the severity and frequency of panic attacks [9, 10]. Several antidepressants demonstrated efficacy in PD, examples of these drugs are imipramine, clomipramine, phenelzine, citalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, and venlafaxine [11-13]. Clinical trials also showed evidences of effectiveness for alprazolam, clonazepam, diazepam, lorazepam, and inositol [11, 12]. Two meta-analyses showed little differences regarding the effectiveness of antidepressants and benzodiazepines, though there were differences in their tolerability [12, 13]. Compared to selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) show a higher dropout rate in © 2014 Bentham Science Publishers
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clinical trials due to their side-effects [13]. Despite being better tolerated than TCA, benzodiazepines have also been considered second choice medications due to their sideeffects profile and risk of dependence [14, 15]. SSRI and serotonin and noradrenaline reuptake inhibitors (SNRI) are probably as effective as TCA and have significantly less side-effects, making them the first choice medications for the treatment of PD [13, 16-19]. Psychoterapy and self-help are effective nonpharmacological treatments for PD [18, 20]. Among psychoterapies the cognitive-behavioral therapy (CBT) is the one with more evidences of effectiveness [14, 18]. This paper summarizes the main clinical studies with pharmacological interventions in PD, alone or in combination with psychotherapy, placing special emphasis on findings that have emerged during the present decade. A literature search was conducted using the databases PubMed, ISI Web of Knowledge and PsycInfo using the following terms: “anti-anxiety agents”, “antidepressive agents”, “antipsychotic agents”, “benzodiazepines”, “clinical trial”, “cognitive therapy”, “comparative studies”, “panic disorder”. The survey was conducted in August 2012, there was no time restriction given for any database. PHARMACOLOGICAL INTERVENTIONS IN PANIC DISORDER Several psychopharmacological agents are available for the treatment of PD, including antidepressants, anxiolytics, anticonvulsants, atypical antipsychotics, CBT adjuvants and other compounds. The effective psychopharmacologial agents in the treatment of PD are summarized in Table 1.
Freire et al.
serotonergic or noradrenergic systems, respectively [13, 24, 25]. Several studies indicated MAOI, TCA, SSRI, SNRI, NRI, and other antidepressants as effective medications in the treatment of PD [13, 19, 24, 25]. Table 1.
Effective compounds in the treatment of PD.
Psychopharmacological Agent
Evidence Strength
SSRI Citalopram
+++
Escitalopram
+++
Fluoxetine
+++
Sertraline
+++
Fluvoxamine
+++
Paroxetine
+++
SNRI Venlafaxine
+++
Duloxetine
+
NRI Reboxetine
+
TCA Imipramine
+++
Clomipramine
+++
TeCA Mirtazapine
++
MAOI
Antidepressants
Phenelzine
Several antidepressants increase serotonergic activity in the central nervous system, which may have inhibitory effects in the locus coeruleus, periaqueductal gray region, and the amygdala itself. Besides that, it reduces the hypothalamic release of corticotropin-releasing factor (CRF), consequently decreasing fear, behavioral and physiological reactions to conditioned stimuli [9]. The noradrenergic system, which is also supposed to be involved in the pathogenesis of PD, is activated in acute stress situations, inducing autonomic arousal, vigilance, and behavioral activation [21, 22]. The lateral bed nucleus of the stria terminalis (BSTL), a component of the extended amygdala, is a major target of noradrenergic innervation, receiving projections from the medulla and locus coeruleus. The BSTL has been implicated in regulation or modulation of behavioral and neuroendocrine responses to stress [21]. Instead of plainly increasing the noradrenergic tonus, noradrenergic antidepressants seem to modulate the noradrenaline releases by means of attenuating the phasic noradrenergic reactivity to stressful or threatening stimuli, and thus producing anxiolytic effect [23, 24]. Many antidepressants have been developed so far, and they are known to potently affect central noradrenergic and/or serotonergic neurons [23]. SNRI, monoamine oxidase inhibitors (MAOI), and some TCA increase both serotonergic and noradrenergic activities, whereas SSRI and noradrenaline reuptake inhibitors (NRI) affect only the
Benzodiazepines
++
Alprazolam
+++
Diazepam
+++
Clonazepam
+++
Lorazepam
+++
Other Nefazodone
+
Risperidone
+
Inositol
++
SRI = selective serotonin reuptake inhibitor; SNRI = serotonin and noradrenaline reuptake inhibitor; NRI = noradrenaline reuptake inhibitor; TCA = tricyclic antidepressant; TeCA = tetracyclic antidepressant ; MAOI = monoamine oxidase inhibitor.
Antidepressant Efficacy The World Federation of Societies of Biological Psychiatry (WFSBP) [11] classified the antidepressants citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, clomipramine, imipramine as category of evidence A in the treatment of PD. This category of evidence means that there were at least two double-blind, parallel-group, randomized controlled trial (RCT) showing superiority to placebo and there was also one or more
Current Pharmacological Interventions in Panic Disorder
CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 6
positive RCT showing superiority to or equivalent efficacy compared with established comparator treatment in a threearm study with placebo control or in a well-powered noninferiority trial. Most of these antidepressants had the highest recommendation grade, but due to a higher risk-benefit ratio, the TCA had the recommendation grade two. The level of evidence for phenelzine was lower due to the scarcity of studies with this compound [11]. The double-blind RCT conducted in the last decade demostrated that fluvoxamine [26], venlafaxine [27-29], paroxetine [28-30], citalopram [31] and escitalopram [31] were effective in the treatment of PD. There was only one RCT indicating that reboxetine was superior to placebo in the treatment of PD [32]. SSRI and SNRI are generally well tolerated and the most common side effects are insomnia, somnolence and dry mouth [19]. Sexual dysfunction is a common side effect of SSRI, occurring in 50% to 80% of the patients [33]. This side effect is also common with SNRI, in a smaller extent [34]. Comparative Studies In most of the recent studies comparing two antidepressants, both active drugs were effective and showed similar antipanic properties [19]. In the comparisons sertraline vs paroxetine [35], sertraline vs imipramine [36, 37], fluoxetine vs clomipramine [38], fluoxetine vs mirtazapine [39], paroxetine vs citalopram [40], paroxetine vs venlafaxine (75 mg and 150 mg) [28, 29], citalopram vs escitalopram [31] both drugs were equally effective. Trials Table 2.
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comparing paroxetine slow-titration vs paroxetine standardtitration [41] and paroxetine vs clonazepam [42] showed similar effectiveness for these treatment regimens, but paroxetine slow-titration and clonazepam induced faster improvements compared to paroxetine standard-titration. In the study from Pollack et al. [29] venlafaxine 75 mg/day and paroxetine 40 mg/day were superior to placebo and equally effective. However, patients treated with venlafaxine 225 mg/day had a superior improvement compared to those treated with paroxetine [29]. Reboxetine [43] and tianeptine [44] had inferior clinical efficacy in the treatment of PD compared to paroxetine. Results from comparative studies are summarized in Table 2. Patients with PD and concurrent major depressive disorder responded significantly and equivalently to both sertraline and imipramine, with substantial improvement in both anxious and depressive symptoms [36]. The studies with TCAs indicated that these medications may induce faster improvement [37, 38], although they frequently cause more side effects than SSRIs, especially dry mouth, constipation, tremors, sweating, and cardiovascular complaints [36, 37]. In an 8-week trial mirtazapine and fluoxetine were both effective in the treatment of PD, but the patients’ perception of their own improvement was significantly better in the mirtazapine group. Patients treated with mirtazapine had more weight gain, whereas those treated with fluoxetine complained more of nausea and paresthesia [39]. One open, randomized and multicenter study [41] compared the therapeutic regimens of paroxetine in slow vs standard titration. The slow-titration group received 2.5 mg
Studies comparing the efficacy of two compounds.
Compound 1
Dose Range (mg/day)
Comparison
Compound 2
Dose Range (mg)
Ref.
Citalopram
20-50
Equivalent
Paroxetine
20-50
[40]
Sertraline
50-150
Equivalent
Paroxetine
40-60
[11]
Sertraline
50-200
Equivalent
Imipramine
1.5 - 2 mg/kg/day
[37]
Sertraline
50-100
Equivalent
Imipramine
100-200
[36]
Paroxetine
40
[28]
Paroxetine
40
[29]
Venlafaxine
75-225
Superior to
Venlafaxine
75-150
Equivalent
a
b
Paroxetine
40
Superior to
Reboxetine
8
[43]
Fluoxetine
60
Equivalent
Clomipramine
75
[38]
Mirtazapine
13-30
Equivalent
Fluoxetine
10-20
[39]
Inositol
18000
Equivalent
Fluvoxamine
150
[69]
Escitalopram
10-20
Equivalent
Citalopram
20-40
[31]
Tianeptine
37.5
[44]
c
Paroxetine
40
Superior to
Paroxetine SLT
20
Equivalent
Paroxetine STT
20
[41]
Clonazepam
0.5-2
Equivalent
Paroxetine
10-40
[42]
Risperidone
0.125-1.0
Equivalent
Paroxetine
30-40
[62]
SLT = Slow titration; STT = Standard titration. a Compared to the paroxetine group the venlafaxine ER 225 mg group had a significantly lower PDSS total score (4.78 vs 6.26; P< 0.05) and a higher percentage of patients free of full-symptom panic attacks (70.0 vs 58.3%; P
