Current pharmacological and non-pharmacological treatments of panic disorder/agoraphobia
Donatella Marazziti, Michela Picchetti, Marina Carlini, Stefano Baroni, Liliana Dell’Osso
Dipartimento Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy
Dr. Donatella Marazziti,
Dipartimento di Psichiatria,
Farmacologia e Biotecnologie,
University of Pisa,
via Roma, 67-I-56100 Pisa, Italy
Article Type: Review Article
Received: June 04, 2012;Accepted: September 01, 2012;Published: October 16, 2012
Citation: Donatella Marazziti (2012) Current Pharmacological and Non-Pharmacological Treatments of Panic Disorder/Agoraphobia.Int J Clin Pharmacol Toxicol. 1(1), 20-25. doi: dx.doi.org/10.19070/2167-910X-120004
Copyright: Donatella Marazziti© 2012. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Anxiety disorders represent the most prevalent psychiatric disorders, however, many patients who might benefit from treatment are not diagnosed or treated. This may partly be due to lack of awareness of the anxiety disorders by primary care practitioners and by the sufferers themselves. In addition, the stigma still associated with psychiatric disorders and lack of confidence in psychiatric treatments are factors leading to no/under recognition and treatment, or the use of unnecessary or inappropriate treatments. This paper aims to provide a comprehensive review of the pharmacological treatment of panic disorders (PD).
The first-line treatments include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Tricyclic antidepressants (TCAs) are similarly effective, but are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines like alprazolam may be used in patients with no history of dependency and tolerance. Other treatment options include irreversible and reversible monoamine-oxidase inhibitors, hydroxyzine, and others. Atypical antipsychotics may also be effective in resistant cases.
Besides pharmacological treatments, some psychological strategies have been shown to be effective, in particular, cognitive behavior therapy (CBT) and other variants of behavior therapy have been sufficiently investigated in controlled studies, and, therefore, will be reviewed herein.
3.1 Tricyclic Antidepressants (TCAs)
3.2 Selective Serotonin Reuptake Inhibitors (Ssris)
3.3 Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
3.4 Benzodiazepines (BDZs)
3.5 Monoamine Oxidase Inhibitors (MAOI)
3.6 Other medications
4.Comparisons of Drugs
6.1 Psychodynamic therapies
Panic Disorder; Tricyclic Antidepressants; Selective Serotonin Re-uptake Inhibitors; Benzodiazepines; Non-Pharmacological Treatment
Panic disorder (PD) is one of the most common anxiety disorders, with a lifetime prevalence of about 5% in the general population and up to 8.3% in clinical settings, and is still associated with relevant impairment of the quality of life . Despite this, there have been only few therapeutic advances in the past years and several critical issues remain open. PD is a heterogeneous psychiatric condition characterized by a discrete period of intense fear or discomfort in the absence of real danger that is accompanied by somatic or cognitive symptoms. The attack has a sudden onset and builds to a peak rapidly, generally in 10 minutes or less, and is accompanied by a sense of imminent danger or impending doom and an urge to escape. The anxiety of PD is different from generalized anxiety, infact the first is discrete, paroxysmal and severe . The disorder is characterized by repeated unexpected panic attacks, persistent anticipatory anxiety and behavioral modification as a direct result of the attacks. A lot of patients show also agoraphobia, often associated with situational panic attacks. PD pathophysiology is still unclear and several potential mechanisms may be involved. Instability of respiratory regulation and/or an abnormally sensitive central neural network of CO2/H+ chemoreception has been implicated both in experimentally induced panic attacks by CO2 inhalation and lactate infusions and in spontaneous panic [3,4]. Crucial advances might be made if panic attacks could be evoked in the laboratory so that the underlying mechanisms might be deconstructed. PD is relatively unique among psychiatric illnesses, in that symptoms resembling the illness can be provoked by a number of chemicals called panicogens. Moreover, the biological mechanisms of the panicogens themselves might tell us a lot about the neurobiology of the illness. Examples of agents with the potential ability to evoke panic attacks include carbon dioxide (CO2), sodium lactate, doxapram, cholecystokinin (CCK-4) and related agonists, flumazenil, caffeine, adrenergic agonists (isoproterenol, yohimbine, epinephrine), serotonin receptor activators (d-fenfluramine, metachlorophenylpiperazine (m-CPP), and perhaps opioid receptor antagonists. The symptoms provoked by these agents can closely resemble naturally occurring attacks . Other mechanisms have been implicating in PD pathophysiology: the inappropriate activation of a central fear network, including the amygdala and its connections with hippocampus, thalamus, hypothalamus as well as the periaqueductal gray region, locus coeruleus and prefrontal cortex; this could result in misinterpretation of sensory harmless information and conditioning processes, leading to panic attacks, anticipatory anxiety and phobic avoidance . Several neurotransmitters play a crucial role in modulating these processes, acting in different CNS areas and influencing each other, and till now the mechanisms of action of the existing anti-panic drugs are not completely understood . In addition, studies have consistently shown that genetic factors explain about half of the variance. The most cases of PD have a complex genetic basis. Several data suggest, however, that the genetic architecture underlying PD is heterogeneous and differs between cases. For example, the degree of genetic complexity, and the pattern of genes involved might differ in familial versus non-familial cases, in early- versus late-onset cases, or when different comorbid conditions, gender and potential intermediate or sub-phenotypes are considered. At the molecular genetic level, linkage and association studies-the latter including traditional candidate gene and recent genome-wide studies-have been used to study PD. Although no molecular genetic findings have emerged so far, it is conceivable that the first PD susceptibility genes will be identified in the future. Such findings could have a major impact on our understanding of the pathophysiology of this disorder, and would provide important opportunities to investigate genotype-phenotype correlations, as well as the interaction between genetic and environmental factors involved in the pathogenesis of PD . PD is a condition characterized by recurring severe panic attacks. These attacks typically last about 10-15 minutes, but can be as short-lived as 1–5 minutes and last as long as 30 minutes or until medical intervention. However, attacks can wax and wane for a period of hours (panic attacks rolling into one another), and the intensity and specific symptoms of panic may vary over the duration. Common symptoms of an attack include rapid heartbeat, perspiration, dizziness, dyspnea, trembling, uncontrollable fear and hyperventilation. Other symptoms are sweating, shortness of breath, sensation of choking, chest pain, nausea, numbness or tingling, chills or hot flashes, and some sense of altered reality. In addition, the patients usually have some thoughts of impending doom. Panic attack can be unexpected (spontaneous) or associated with a situational triggers that can include internal (e.g., physiological arousal) or external (e.g., a phobic object or situation) stimuli to the subject. The patients fear the implication or consequences of the panic attacks, the presence of an undiagnosed or severe illness, to became crazy, to lose the control. Individuals suffering from an episode have often a strong wish of escaping from the situation that provoked the attack. It may also include significant behavioral change lasting at least a month and of ongoing worries about the implications or concerns about developing other attacks.
The frequency and the severity of the panic attacks is variable. Some patients show a course characterized by attacks that occur regularly once a week, others more frequent attacks (daily) separate by weeks or months without any episode or with less frequent attacks over many years.
PD is a chronic and debilitating condition associated with a high rate of relapse and co-morbidity, including other anxiety and affective disorders, suicide attempts, abuse of psychoactive substances and cardiovascular diseases . Between 20 and 40% of patients with PD do not fully respond to pharmacotherapy, although when recommended medications are used and the doses and the length of treatment are adequate. Similarly, 30-40% of patients with PD and agoraphobia do not achieve significant improvement with cognitive behavioral therapy (CBT) and so far the combination of CBT and pharmacotherapy does not appear to fill this gap . In addition, 25 -50%, of patients relapse within 6 months after drug discontinuation and up to 40-50% of subjects still have residual panic-phobic symptoms and up to 20-30 % still have full-blown disorder after 3 -6 years; finally, the maintenance of benefit following therapy discontinuation appears to be more influenced by the attainment of a complete remission before interruption than the duration of treatment, underscoring the relevance of maximizing improvement obtained from initial pharmacotherapy .
When severe, these symptoms can be debilitating, particularly for the large number of patients who are refractory to current therapies. Identifying new therapies may require understanding of why panic attacks occur and what triggers them, knowledge that is currently lacking.
The present paper aims to present a comprehensive review of those pharmacological and non-pharmacological strategies most often adopted in PD, focusing especially on those pharmacological treatments which appear most promising.
It has been widely demonstrated that PD may symptoms may improve with TCAs, in particular with imipramine and clomipramine. In any case, adverse events are reported more frequently than with the SSRIs, so that these latter are now the first-line drugs for the treatment of PD [12-18].
Imipramine resulted effective in PD since some decades ago [19-21] in double-blind, placedo controlled and in comparator-controlled studies [22-25]. It was more effective than placebo and equally effective as alprazolam in one relapse-prevention study (acute study over 8 weeks, followed by up to 35 weeks relapse-prevention) . In another trial, it was as effective as alprazolam for 8 weeks, but less effective than alprazolam in a 26-week double-blind, placedo controlled extension . In a 26-week long-term study, it was seen to be as effective as fluoxetine .
Clomipramine demonstrated a similar efficacy of imipramine in double-blind, placedo controlled [28,29] and in comparator-controlled studies [18,30-33]. It was as effective as the SSRI paroxetine in a relapse-prevention trial performed over 36 weeks .
In several controlled studies, SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram) have been shown to be significantly effective in PD, and are currently considered as the first-line drugs for the treatment of this disorder. Single compounds will be received separately, as follows.
Fluoxetine showed efficacy in The Fluoxetine Panic Disorder Study Group [34,35], as well as in comparator-controlled trials [15,36]. It proved as effective as imipramine in one 26-week long-term study . It was also seen to be as effective as the RIMA moclobemide in a 52-week long-term study .
Fluvoxamine was shown to be effective in a number of The Fluvoxamine Panic Disorder Study Group [38-43]. In one study, fluvoxamine and the comparator imipramine proved equally effective, and both were seen to be more effective than placebo . No superiority over placebo was demonstrated on the main efficacy measure in one small study, although it was seen on some other instruments . In another study, fluvoxamine showed no efficacy, at variance with imipramine .
Paroxetine demonstrated efficacy both in double-blind, placedo controlled trials [45-48] and in comparator-controlled studies [14,32,46,49-51]. It also proved as effective as clomipramine in a 36-week relapse-prevention trial .
Sertraline was shown to be effective in double-blind, placedo controlled studies [52-54], as well as in one comparator trial . Sertraline was superior tha nplacebo in a relapse-prevention study carried out over 26 weeks and followed by an open fashion over 1 year . In another relapse-prevention study responders after 8-weeks of controlled study were randomized to sertraline or placebo. Except for the relapse rate, sertraline was better than placebo on most measures . Sertraline was superior to placebo and as effective as imipramine in patients with panic disorder and comorbid depression in a 26-week long-term study .
Citalopram was effective in a placebo- and comparator-controlled trial , and in one comparison with fluoxetine . It was shown to be superior to placebo and as effective as the clomipramine in a relapse-prevention study carried out over 52 weeks . It was also shown to be as effective as fluoxetine in a long-term study in which a double-blind treatment was performed for 24 weeks followed by an open extension of another 26 weeks .
Escitalopram resulted to be effective in a citalopram- and placebo-controlled trial [58,59]. Because escitalopram is the S-enantiomer of the racemate citalopram, it may be that the clinical studies with citalopram are also relevant for escitalopram
The SNRI venlafaxine was shown to be effective in double-blind, placedo controlled studies [60,61]. In several trials, an association was detected with a lower frequency of mean panic attack, with a higher proportion of subjects free of symptoms, with higher response and remission rates. Venlafaxine was also shown to be more effective than placebo and equally effective as the comparator drug paroxetine in two studies [50,62]. In one relapse-prevention study, 12 weeks of open treatment with venlafaxine were followed by 26 weeks of D double-blind, placedo controlled treatment , and the drug proved more effective than placebo in preventing relapses. The new formulation slow-release venlafaxine is potentially promising, but no.
In a number of controlled clinical studies, BDZs have demonstrated effectiveness in PD
Alprazolam was equal in effect to comparator drugs and superior to placebo in several studies [22,25,64-67]. In one relapse-prevention study featuring 8 weeks acute study followed by relapse-prevention of up to 35 weeks, it resulted to be more effective than placebo and just as effective as imipramine . Another relapse-prevention study saw it equally as effective as imipramine in an 8-week acute DBPC study, and superior in effect to imipramine in a 26-week The Fluoxetine Panic Disorder Study Group extension .
Diazepam was more effective than placebo and similar to alprazolam in two studies [67,75].
Generally BDZs are commonly combined with SSRIs, SNRIs or TCAs in the clinical practice mainly in the initial phases. In one study aimed at examining this combination, patients were treated with either paroxetine and clonazepam or with paroxetine and placebo. Paroxetine and clonazepam in combination resulted in a more rapid response with the SSRI alone, although no differential benefit was demonstrated in the next weeks . The combination, of imipramine and alprazolam , or of sertraline and clonazepam  led to similart findings.
However, the use of BDZs, should be limited at the acute phases of PD for the risk of abuse, development of tolerance and onset of severe side effects, as well as withdrawl symptoms.
Although phenelzine is widely used in PD, the evidence is only based on a single study  showing that it was more effective than placebo and equal to, or even superior to (according to some measures), imipramine.
Some available drugs have shown some preliminary evidence of effectiveness or have given mixed results. These drugs are used “off-label” by some practitioners in patients who did not respond to standard treatments.
The reversible inhibitor of monoamine oxidase (RIMA), moclobemide, yielded inconsistent results, as it appeared to be effective or not in different trials [37,80-82]. It is available in Canada, but not in US and in other countries. Among its side effects are restlessness, insomnia, dry mouth, and headache.
Reboxetine, a norepinephrine reuptake inhibitor (NARI) was shown to be effective in a controlled study . It was as effective as fluvoxamine in single-blind studies , but was not effective as paroxetine .
Inconsistent data are available for mirtazapine , and two anticonvulsants, valproate , and gabapentin , and bupropion, a norepinephrine-dopamine reuptake inhibitor .
The intracellular second-messenger precursor inositol demonstrated superiority compared to placebo in a small DBPC study  , and was as effective as the SSRI fluvoxamine .
Buspirone demonstrated no superiority to placebo in panic disorder [92,93], and was found less effective than imipramine , clorazepate , and alprazolam .
Beta blockers, such as propanolol, have been employed in the treatment of PD, because they may influence autonomic anxiety symptoms, such as palpitations, tremor, etc, however, their real effectiveness remains to be demonstrated [95,96].
Comparisons of Drugs
No differences could be found between TCAs and SSRIs in studies comparing their efficacy [12-14,18], except for maprotiline, which demonstrated no effect when compared to fluvoxamine . The SSRIs were seen to be better tolerated than the TCAs in most of these studies, although one analysis found no difference regarding tolerability between SSRIs and imipramine . Further, sertraline and imipramine were equally effective in patients with comorbid PD and major depressive disorder, although sertraline demonstrated a significantly greater degree of tolerability and compliance than did imipramine .
Some studies which compared SSRIs revealed no differences regarding their efficacy [46,99], while on some outcome measures escitalopram showed evidence of superiority over citalopram .
In the treatment of PD there are no direct comparisons between SSRIs and BDZs. A meta-analysis showed that the amplitude of the effect was greater for SSRIs than for alprazolam .
Several studies compared alprazolam with imipramine but no differences were found between the two drugs [22,25,64,101-104].
Only a few studies have been performed with treatment-resistant PD patients. The only existing preliminary controlled study demonstrated an augmenting effect of pindolol on fluoxetine in patients with treatment-resistant panic disorder .
When an initial treatment fails, patients should first be switched to other first-line standard treatments, e.g. from an SSRI to an SNRI or viceversa. Because the SSRIs are chemically different compounds, a switch from one SSRI to another can be justified . The next step should be the use of second-line drugs, such as TCAs. Finally, drugs or drug combinations which showed efficacy in open studies and case reports may be an option.
In one study in which there was no control condition, patients presenting residual symptoms despite treatment with a sufficient dose of medication showed improvement following the introduction of CBT [107,108]. Conversely, patients in whom an insufficient response to CBT was seen can show improvement with SSRIs or clomipramine [109,110].
Amongst non-pharmacological treatments, cognitive behavioral therapy (CBT) has been investigated thoroughly in PD. Agoraphobia is generally treated with exposure therapy and cognitive therapy, including interoceptive exposure was developed for the treatment of spontaneous panic attacks [111,112].
In the majority of the studies on PD and/or agoraphobia, CBT resulted superior to waiting-list control condition [113-121].
Several trials reported the superiority of CBT to a pill placebo or a psychological- placebo [112,115,122-127], while others detected no difference to the control condition [14,39,128-130]. Three studies comparing CBT or exposure therapy with psychopharmacological treatment, reported drugs to be superior than other strategies [14,39,128]. However, controversial data are also available [112,114,125,131-134]. In any case, the combination of CBT+drug has proven to be more effective than psychological therapy alone in most studies [20,21,40,46,112,122,128,133,135,136], except that in two [125,132]. The combination of CBT or psychodynamic treatment with a drug was seen to be superior to drug alone in two studies [137,138], while in three studies no difference was found between the combination and CBT alone [122,125,132].
Several meta-analyses regarding the efficacy of the psychological and pharmacological treatment of anxiety disorders have yielded contradictory results [139-149]. Such inconsistent results seem, for the most part, to stem from the inclusion of heterogeneous studies and the influence of selection biases. A recent and accurate meta-analysis highlighted the efficacy of the combination .
Only a limited number of studies have evaluated psychodynamic psychotherapy or other forms of psychotherapies in PD, so that no conclusion can be drawn on the effectiveness of these strategies [151-153].
Drugs used in PD include TCAs SSRIs, SNRIs, BDZs, and MAOI [154,155]. SSRIs affect mainly the serotonergic system, while SNRIs and some TCAs modulate both serotonergic and noradrenergic activities, BDZs affect the GABA system, and some of these drugs may have secondary effects also on other neurotransmitters. The effectiveness of these drugs is due to their effects on several brain pathways potentially involved in pathophysiology of PD including areas of the brain involved in control of ventilation and acid—base balance and in emotional responses, arousal and defensive behaviors, including brainstem respiratory network, the nucleus tractus solitarii, the medullary and midbrain raphe neurons, the amygdala and the hypothalamus, both having CO2/H+ sensitive neurons, and the periaqueductal gray .
Despite the wide variety of drugs available, some patients show a partial response, or frequent relapses or even they are refractory. The drugs for PD do not obtain full clinical responses in all of the treated patients and it is still unclear if the more recent compounds with dual mechanisms of action on serotonergic and noradrenergic systems will be able to increase significantly the clinical response. Because serotonin, noradrenaline and GABA act as parts of a complex network including other neurotransmitters and multiple levels of modulation, it has been hypothesized that compounds having new mechanisms of action and/or acting simultaneously on a broader group of neurotransmitters may better respond to the medical needs of patients with PD.
Future research for the treatment of PD are focusing on the development of new compounds with novel mechanisms of action and, the potential efficacy of existing drugs, already used for treatment of other psychiatric disorders, with different pharmacodynamic profiles compared to standard drugs for PD. For example glutamate is the excitatory neurotransmitter in the mammalian brain and the modulation of glutamatergic excitatory amino-acid transmission potentially represents a new approach to treat a number of neurological and psychiatric conditions, including PD . The metabotropic glutamate receptors (mGlu) are a novel class of receptors under investigation that modulate glutamatergic neurotransmission by regulating the glutamate release at presynaptic sites or neuronal excitability at postsynaptic sites, and they are localized in the cortex, hippocampus, limbic areas, brainstem and cerebellar regions, suggesting their implication in anxiety responses, emotions and cognition in animal and humans . Preclinical studies showed mGlu receptor agonists may have potential clinical utility in modulating different phenomena in PD, including panic attacks and phobic conditions, with a favorable side effect profile. Recent and scattered data suggest that other intervention possibilities may be associated with modulation of second messengers and opioids. This has led to the proposal of new compounds, in particular inositol, D-cycloserine, riluzole, memantine and morphine, with these demonstrating a certain degree of effectiveness.
The pharmacological research on PD appears to be relatively limited, infact clinical pictures of PD is heterogeneous, but, in clinical trials patients with PD are classified only according to current descriptive nosographical criteria and are considered as a homogeneous group. Moreover trials were performed involving only small patient populations, and have mostly been open-label, so that the ensuing findings should be viewed as preliminary. Similarly, the effectiveness of non-pharmacological strategies remains to be demonstrated, except that for CBT that it is now recognized as a first-line treatment in OCD by several guidelines. However, only a deeper understanding of the biological mechanisms underlying anxiety might permit the development of more targeted and effective compounds beyond the 5-HT system.
- Westenberg HGM, Liebowitz MR (2004) Overview of panic and social anxiety disorders. J Clin Psychiatry 65:22-26.
- American Psychiatric Association 1994 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Press: Washington, DC.
- Klein DF 1993 False suffocation alarms, spontaneous panics,and related conditions. An integrative hypothesis. Arch Gen Psychiatry 50:306-317.
- Esquivel G, Schruers KR, Maddock RJ, Colasanti A, Griez EJ (2010) Acids in the brain: a factor in panic? J Psychopharmacol 24:639-647.
- Wemmie JA (2011) Neurobiology of panic and pH chemosensation in the brain. Dialogues Clin Neurosci 13(4): 475-483.
- Gorman JM, Kent JM, Sullivan GM, Coplan JD (2000) Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 157:493-505.
- Freire RC, Hallak JE, Crippa JA, Nardi AE (2011) New treatment options for panic disorder: clinical trials from 2000 to 2010. Expert Opin Pharmacother 12:1419-1428.
- Schumacher J, Kristensen AS, Wendland JR, Nöthen MM, Mors O, McMahon FJ (2011) The genetics of panic disorder. J Med Genet 48(6):361-368.
- Yates WR (2009) Phenomenology and epidemiology of panic disorder. Ann Clin Psychiatry 21:95-102.
- Van Apeldoorn FJ, van Hout WJPJ, Mersch PP, Huisman M, Slaap BR (2008) Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia. Acta psychiatr Scand 117: 260-270.
- American Psychiatric Association (2009) Practice guideline for the treatment of patients with panic disorder. 2nd edition. American Psychiatric Publishing, Inc.; Washington, DC.
- Amore M, Magnani K, Cerisoli M, Casagrande C, Ferrari G (1999) Panic disorder. A long-term treatment study: Fluoxetine vs imipramine. Hum Psychopharmacol Clin Exp 14: 429-434.
- Bakish D, Hooper CL, Filteau MJ, Charbonneau Y, Fraser G, et al. (1996) A double-blind placebo-controlled trial comparing fluvoxamine and imipramine in the treatment of panic disorder with or without agoraphobia. Psychopharmacol Bull 32: 135-1341.
- Bakker A, van Dyck R; Spinhoven P, van Balkom A (1999) Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder. J Clin Psychiatry 60: 831-838.
- Bystritsky A, Rosen RM, Murphy KJ, Bohn P, Keys SA, et al. (1994) Double-blind pilot trial of desipramine versus fluoxetine in panic patients. Anxiety 1: 287-290.
- Lecrubier Y, Judge R (1997) Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand 95: 153-160.
- Lepola UM, Wade AG, Leinonen EV, Koponen HJ, Frazer J, et al. (1998) A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder. J Clin Psychiatry 59: 528-534.
- Wade AG, Lepola U, Koponen HJ, Pedersen V, Pedersen T (1997) The effect of citalopram in panic disorder. Br J Psychiatry 170: 549-553.
- 19. Klein D (1964) Delineation of two drug-responsive anxiety syndromes. Psychopharmacology 5: 397-408.
- Zitrin, C.M.; Klein, D.F.; Woerner, M.G. Treatment of agoraphobia with group exposure in vivo and imipramine. Arch. Gen. Psychiatry, 1980; 37, 63-72.
- Zitrin CM, Klein DF, Woerner MG, Ross DC (1983) Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatry 40: 125-138.
- CNCPS Cross-national collaborative panic study (1992) Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. Br J Psychiatry 160: 191-202.
- Nair NP, Bakish D, Saxena B, Amin M, Schwartz G, et al. (1996) Comparison of fluvoxamine, imipramine, and placebo in the treatment of outpatients with panic disorder. Anxiety 2: 192-198.
- Sheehan DV, Raj AB, Sheehan KH, Soto S (1990) Is buspirone effective for panic disorder? J Clin Psychopharmacol 10: 3-11.
- Uhlenhuth EH, Matuzas W, Glass RM, Easton C (1989) Response of panic disorder to fixed doses of alprazolam or imipramine. J Affect Disord 17: 261-270.
- Curtis GC, Massana J, Udina C, Ayuso JL, Cassano GB, et al. (1993) Maintenance drug therapy of panic disorder. J Psychiatr Res 27: 127-142.
- Rickels K, Schweizer, E (1998) Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol 18: 12S-18S.
- Bandelow B, Broocks A, Pekrun G, George A, Meyer T, et al. (2000) The use of the Panic and Agoraphobia Scale (P & A) in a controlled clinical trial. Pharmacopsychiatry 33: 174-181.
- Johnston D, Troyer I, Whitsett S (1988) Clomipramine treatment of agoraphobic women. An eight-week controlled trial. Arch Gen Psychiat 45: 453-459.
- Cassano GB, Petracca A, Perugi G, Nisita C, Musetti L, et al. (1988) Clomipramine for panic disorder: I. The first 10 weeks of a long-term comparison with imipramine. J Affect Disord 14: 123-127.
- Fahy TJ, O'Rourke D, Brophy J, Schazmann W, Sciascia S (1992)The Galway Study of Panic Disorder. I: Clomipramine and lofepramine in DSM III-R panic disorder: a placebo controlled trial. J Affect Disord 25: 63-75.
- Lecrubier Y, Bakker A, Dunbar G, Judge R (1997) A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand 95: 145-152.
- Modigh K, Westberg P, Eriksson E (1992) Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial. J Clin Psychopharmacol 12: 251-261.
- Michelson D, Lydiard RB, Pollack MH, Tamura RN, Hoog SL, et al. (1998) Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group. Am J Psychiatry 155: 1570-1577.
- Michelson D, Allgulander C, Dantendorfer K, Knezevic A, Maierhofer D, et al. (2001) Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder: randomised, placebo-controlled trial. Br J Psychiatry 179: 514-518.
- Amore M, Magnani K, Cerisoli M, Ferrari G (1999) Short-term and long-term evaluation of selective serotonin reuptake inhibitors in the treatment of panic disorder: fluoxetine vs citalopram. Hum. Psychopharmacol Clin Exp 14: 435-440.
- Tiller JW, Bouwer C, Behnke K (1999) Moclobemide and fluoxetine for panic disorder. International Panic Disorder Study Group. Eur Arch Psychiatry Clin Neurosci 249: S7-10.
- Asnis GM, Hameedi FA, Goddard AW, Potkin SG, Black D, et al. (2001) Fluvoxamine in the treatment of panic disorder: a multi-center, double-blind, placebo-controlled study in outpatients. Psychiatry Res 103: 1-14.
- Black DW, Wesner R, Bowers W, Gabel J (1993) A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 50: 44-50.
- de Beurs E, van Balkom AJ, Lange A, Koele P, van Dyck R (1995) Treatment of panic disorder with agoraphobia: comparison of fluvoxamine, placebo, and psychological panic management combined with exposure and of exposure in vivo alone. Am J Psychiatry152: 683-691.
- den Boer JA, Westenberg HG (1990) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology Berl 102: 85-94.
- Hoehn-Saric R, McLeod DR, Hipsley PA (1993) Effect of fluvoxamine on panic disorder. J Clin Psychopharmacol 13: 321-326.
- Pols H, Zandergen J, de Loof C, Fernandez I, Griez E (1993) Clinical effects of fluvoxamine on panic symptomatology. Acta Psychiatr Belg 93: 169-177.
- Sandmann J, Lorch B, Bandelow B, Hartter S, Winter P, et al. (1998) Fluvoxamine or placebo in the treatment of panic disorder and relationship to blood concentrations of fluvoxamine. Pharmacopsychiatry 31: 117-121.
- Ballenger JC, Wheadon DE, Steiner M, Bushnell W, Gergel IP (1998) Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry 155: 36-42.
- Oehrberg S, Christiansen PE, Behnke K, Borup AL, Severin B, et al. (1995). Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study. Br J Psychiatry 167: 374-379.
- Pollack MH, Doyle AC (2003) Treatment of panic disorder: focus on paroxetine. Psychopharmacol Bull 37: 53-63.
- Sheehan DV, Burnham DB, Iyengar MK, Perera P (2005) Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. J. Clin. Psychiatry, 2005; 66, 34-40.
- Bandelow B, Behnke K, Lenoir S, Hendriks GJ, Alkin T, et al. (2004) Sertraline Versus Paroxetine in the Treatment of Panic Disorder: An Acute, Double-Blind Noninferiority Comparison. J Clin Psychiatry 65: 405-413.
- Pollack M.H, Lepola U, Koponen H, Simon NM, Worthington JJ, et al. (2007) A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder. Depress Anxiety 24: 1-14.
- Wedekind D, Broocks A, Weiss N, Engel K, Neubert K, et al. (2010) A randomized, controlled trial of aerobic exercise in combination with paroxetine in the treatment of panic disorder. World J Biol Psychiatry 11: 904-913.
- Londborg PD, Wolkow R, Smith WT, DuBoff E, England D, et al. (1998) Sertraline in the treatment of panic disorder - A multi-site, double-blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 173: 54-60.
- Pohl RB, Wolkow RM, Clary CM (1998) Sertraline in the treatment of panic disorder: A double-blind multicenter trial. Am J Psychiatry 155: 1189-1195.
- Pollack MH, Otto MW, Worthington JJ, Manfro GG, Wolkow R (1998) Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial. Arch Gen Psychiatry 55: 1010-1016.
- Rapaport MH, Wolkow R, Rubin A, Hackett E, Pollack M, et al. (2001) Sertraline treatment of panic disorder: results of a long-term study. Acta Psychiatr Scand 104: 289-298.
- Kamijima K, Kuboki T, Kumano H, Burt T, Cohen G, et al. (2005) A placebo-controlled, randomized withdrawal study of sertraline for panic disorder in Japan. Int Clin Psychopharmacol 20: 265-273.
- Lepola U, Arato M, Zhu Y, Austin C (2003) Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder. J Clin Psychiatry 64: 654-662.
- Bandelow B, Stein DJ, Dolberg OT, Andersen HF, Baldwin DS (2007) Improvement of quality of life in panic disorder with escitalopram, citalopram, or placebo. Pharmacopsychiatry 40: 152-156.
- Stahl SM, Gergel I, Li D (2003) Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 64: 1322-1327.
- Bradwejn J, Ahokas A, Stein DJ, Salinas E, Emilien G,et al. (2005) Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry 187: 352-359.
- Pollack MH, Worthington JJ, Otto MW, Maki KM, Smoller JW, et al. (1996) Venlafaxine for panic disorder: results from a double-blind, placebo-controlled study. Psychopharmacol Bull 32: 667-670.
- Pollack M, Mangano R, Entsuah R, Tzanis E, Simon NM, et al. (2007) A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder. Psychopharmacol Berl 194: 233-242.
- Ferguson JM, Khan A, Mangano R, Entsuah R, Tzanis E (2007) Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release. J Clin Psychiatry 68: 58-68.
- Andersch S, Rosenberg NK, Kullingsjo H, Ottosson JO, Bech P, et al. (1991) Efficacy and safety of alprazolam, imipramine and placebo in treating panic disorder. A Scandinavian multicenter study. Acta Psychiatr Scand 365: 18-27.
- Ballenger JC, Burrows GD, DuPont RLJr, Lesser IM, Noyes RJr, et al. (1988) Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 45: 413-422.
- Lydiard RB, Lesser IM, Ballenger JC, Rubin RT, Laraia M, et al. (1992) A fixed-dose study of alprazolam 2 mg, alprazolam 6 mg, and placebo in panic disorder. J Clin Psychopharmacol 12: 96-103.
- Noyes RJr, Burrows GD, Reich JH, Judd FK, Garvey MJ, et al. (1996) Diazepam versus alprazolam for the treatment of panic disorder. J Clin Psychiatry 57: 349-355.
- Beauclair L, Fontaine R, Annable L, Holobow N, Chouinard G (1994) Clonazepam in the treatment of panic disorder: a double-blind, placebo-controlled trial investigating the correlation between clonazepam concentrations in plasma and clinical response. J Clin Psychopharmacol 14: 111-118.
- Dyukova GM, Shepeleva IP, Vorob'eva OV (1992) Treatment of negative crises (panic attacks). Neurosci Behav Physiol 22: 343-345.
- Moroz G, Rosenbaum JF (1999) Efficacy, safety, and gradual discontinuation of clonazepam in panic disorder: a placebo-controlled, multicenter study using optimized dosages. J Clin Psychiatry 60: 604-612.
- Rosenbaum JF, Moroz G, Bowden CL (1997) Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic Disorder Dose-Response Study Group. J Clin Psychopharmacol 17: 390-400.
- Tesar GE, Rosenbaum JF, Pollack MH, Otto MW, Sachs GS, et al. (1991) Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder. J Clin Psychiatry 52: 69-76.
- Charney DS, Woods SW (1989) Benzodiazepine treatment of panic disorder: a comparison of alprazolam and lorazepam. J Clin Psychiatry 50: 418-423.
- Schweizer E, Pohl R, Balon R, Fox I, Rickels K, et al. (1990) Lorazepam vs. alprazolam in the treatment of panic disorder. Pharmacopsychiatry 23: 90-93.
- Dunner DL, Ishiki D, Avery DH, Wilson LG, Hyde TS (1986) Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. J Clin Psychiatry 47: 458-460.
- Pollack MH, Simon NM, Worthington JJ, Doyle AL, Peters P, et al. (2003) Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol 17: 276-282.
- Woods SW, Nagy LM, Koleszar AS, Krystal JH, Heninger GR, et al. (1992) Charney, D.S. Controlled trial of alprazolam supplementation during imipramine treatment of panic disorder. J Clin Psychopharmacol 12: 32-38.
- Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, et al. (2001) Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry 58: 681-686.
- Sheehan DV, Ballenger J, Jacobsen G (1980) Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Arch Gen Psychiatry 37: 51-59.
- Krüger MB, Dahl AA (1999) The efficacy and safety of moclobemide compared to clomipramine in the treatment of panic disorder. Eur Arch Psychiatry Clin Neurosci 249: S19-24.
- Loerch B, Graf-Morgenstern M, Hautzinger M, Schlegel S, Hain C, et al. (1999) Randomised placebo-controlled trial of moclobemide, cognitive- behavioural therapy and their combination in panic disorder with agoraphobia. Br J Psychiatry 174: 205-212.
- Uhlenhuth EH, Warner TD, Matuzas W (2002) Interactive model of therapeutic response in panic disorder: moclobemide, a case in point. J Clin Psychopharmacol 22: 275-284.
- Versiani M, Cassano GB, Perugi G, Benedetti A, Mastalli L, et al. (2002) Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. J Clin Psychiatry 63: 31-37.
- Seedat S, van Rheede van Oudtshoorn E, Muller JE, Mohr N, Stein DJ (2003) Reboxetine and citalopram in panic disorder: a single-blind, cross-over, flexible-dose pilot study. Int Clin Psychopharmacol 18: 279-284.
- Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, et al. (2004) Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study. Pharmacopsychiatry 37: 206-210.
- Ribeiro L, Busnello JV, Kauer-Sant'Anna M, Madruga M, Quevedo J, et al. (2001) Mirtazapine versus fluoxetine in the treatment of panic disorder. Braz J Med Biol Res 34: 1303-1307.
- Lum M, Fontaine R, Elie R, Ontiveros A (1990) Divalproex sodium's antipanic effect in panic disorder: a placebo-controlled study. Biol Psychiatry 27: 164A-165A.
- Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, et al. (2000) Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 20: 467-471.
- Sheehan DV, Davidson J, Manschreck T, Van Wyck Fleet J (1983) Lack of efficacy of a new antidepressant (bupropion) in the treatment of panic disorder with phobias. J Clin Psychopharmacol 3: 28-31.
- Benjamin J, Levine J, Fux M, Aviv A, Levy D, et al. (1995) Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152: 1084-1086.
- Palatnik A, Frolov K, Fux M, Benjamin J (2001) Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21: 335-339.
- Sheehan DV, Raj AB, Sheehan KH, Soto S (1990) Is buspirone effective for panic disorder? J Clin Psychopharmacol 10: 3-11.
- Sheehan DV, Raj AB, Sheehan KH, Soto S, Knapp E (1993) The relative efficacy of high-dose buspirone and alprazolam in the treatment of panic disorder: a double-blind placebo-controlled study. Acta Psychiatr Scand 88: 1-11.
- Schweizer E, Rickels K (1988) Buspirone in the treatment of panic disorder: a controlled pilot comparison with clorazepate [letter]. J Clin Psychopharmacol 8: 303.
- Munjack DJ, Crocker B, Cabe D, Brown R, Usigli R, et al. (1989) Alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks. J Clin Psychopharmacol 9: 22-27.
- Noyes RJr, Anderson DJ, Clancy J, Crowe RR, Slymen DJ, et al. (1984) Diazepam and propranolol in panic disorder and agoraphobia. Arch Gen Psychiatry 41: 287-292.
- den Boer JA, Westenberg HG (1988) Effect of a serotonin and noradrenaline uptake inhibitor in panic disorder; a double-blind comparative study with fluvoxamine and maprotiline. Int Clin Psychopharmacol 3: 59-74.
- Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH (2001) An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry 158: 1989-1992.
- Perna G, Bertani A, Caldirola D, Smeraldi E, Bellodi L (2001) A comparison of citalopram and paroxetine in the treatment of panic disorder: a randomized, single-blind study. Pharmacopsychiatry 34: 85-90.
- Boyer W (1995) Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks: a meta-analysis. Int Clin Psychopharmacol: 10, 45-49.
- Charney DS, Woods SW, Goodman WK, Rifkin B, Kinch M, et al. (1986) Drug treatment of panic disorder: the comparative efficacy of imipramine, alprazolam, and trazodone. J Clin Psychiatry 47: 580-586.
- Lepola U, Heikkinen H, Rimon R, Riekkinen P (1990) Clinical evaluation of alprazolam in patients with panic disorder a double-blind comparison with imipramine. Human Psychopharmacol 5: 159-163.
- Rizley R, Kahn RJ, McNair DM, Frankenthaler LM (1986) A comparison of alprazolam and imipramine in the treatment of agoraphobia and panic disorder. Psychopharmacol Bull 22: 167-172.
- Taylor CB, Hayward C, King R, Ehlers A, Margraf J, et al. (1990) Cardiovascular and symptomatic reduction effects of alprazolam and imipramine in patients with panic disorder: results of a double-blind, placebo-controlled trial. J Clin Psychopharmacol 10: 112-118.
- Hirschmann S, Dannon PN, Iancu I, Dolberg OT, Zohar J, et al. (2000) Pindolol augmentation in patients with treatment-resistant panic disorder: A double-blind, placebo-controlled trial. J Clin Psychopharmacol 20: 556-559.
- Bandelow B, Rüther E (2004) Treatment-resistant panic disorder. CNS Spectr 9: 725-739.
- Heldt E, Manfro GG, Kipper L, Blaya C, Maltz S, et al. (2003) Treating medication-resistant panic disorder: predictors and outcome of cognitive-behavior therapy in a Brazilian public hospital. Psychother Psychosom 72: 43-48.
- Pollack MH, Otto MW, Kaspi SP, Hammerness PG, Rosenbaum JF (1994) Cognitive behavior therapy for treatment-refractory panic disorder. J Clin Psychiatry 55: 200-205.
- Hoffart A, Due Madsen J, Lande B, Gude T, Bille H, et al. (1993) Clomipramine in the treatment of agoraphobic inpatients resistant to behavioral therapy. J Clin Psychiatry 54: 481-487.
- Kampman M, Keijsers GP, Hoogduin CA, Hendriks GJ (2002) A randomized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. J Clin Psychiatry 63: 772-777.
- Barlow D (1997) Cognitive-behavioral therapy for panic disorder: current status. J Clin Psychiatry 58: 32-37.
- Marks IM, Swinson RP, Basoglu M, Kuch K, Noshirvani H, et al. (1993). Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. Br J Psychiatry 162: 776-787.
- Barlow D, Craske M, Cerny J, Klosko J (1989) Behavioral treatment of panic disorder. Behav Ther 20; 261-282.
- Klosko JS, Barlow DH, Tassinari R, Cerny JA (1990) A comparison of alprazolam and behavior therapy in treatment of panic disorder. J Consult Clin Psychol 58: 77-84.
- Lidren DM, Watkins PL, Gould RA, Clum GA, Asterino M, et al. (1994) A comparison of bibliotherapy and group therapy in the treatment of panic disorder. J Consul Clin Psychol 62: 865-869.
- Margraf J, Barlow DH, Clark DM, Telch MJ (1993) Psychological treatment of panic: work in progress on outcome, active ingredients, and follow-up. Behav Res Ther 31: 1-8.
- Swinson RP, Fergus KD, Cox BJ, Wickwire K (1995) Efficacy of telephone-administered behavioral therapy for panic disorder with agoraphobia. Behav Res Ther 33: 465-469.
- Telch MJ, Lucas JA, Schmidt NB, Hanna HH, LaNae Jaimez T, et al. (1993) Group cognitive-behavioral treatment of panic disorder. Behav Res Ther 31: 279-287.
- Telch MJ, Schmidt NB, Jaimez TL, Jacquin KM, Harrington PJ (1995) Impact of cognitive-behavioral treatment on quality of life in panic disorder patients. J Consult Clin Psychol 63: 823-830.
- Williams SL, Falbo J (1996) Cognitive and performance-based treatments for panic attacks in people with varying degrees of agoraphobic disability. Behav Res Ther 34: 253-264.
- Gould RA, Clum GA, Shapiro D (1993) The use of bibliotherapy in the treatment of panic: a preliminary investigation. Behav Ther 24: 241-252.
- Barlow DH, Gorman JM, Shear MK, Woods SW (2000) Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. Jama 283: 2529-2536.
- Beck AT, Sokol L, Clark DA, Berchick R, Wright F (1992) A crossover study of focused cognitive therapy for panic disorder. Am J Psychiatry 149: 778-83.
- Carlbring P, Bohman S, Brunt S, Buhrman M, Westling BE, et al. (2006). Remote treatment of panic disorder: a randomized trial of internet-based cognitive behavior therapy supplemented with telephone calls. Am J Psychiatry 163: 2119-2125.
- Marks IM, Gray S, Cohen D, Hill R, Mawson D, et al. (1983) Imipramine and brief therapists-aided exposure in agoraphobics having self-exposure homework. Arch Gen Psychiatry 40: 153-162.
- Mavissakalian M, Michelson L (1983) Agoraphobia: behavioral and pharmacological treatment (n=49). Psychopharmacol Bull 19: 116-118.
- Murphy MT, Michelson LK, Marchione K, Marchione N, Testa S (1998) The role of self-directed in vivo exposure in combination with cognitive therapy, relaxation training, or therapist-assisted exposure in the treatment of panic disorder with agoraphobia. J Anxiety Disord 12: 117-138.
- Mavissakalian M, Michelson L (1986) Agoraphobia--relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. J Clin Psych 47: 117-122.
- Michelson L, Mavissakalian M, Marchione K (1988) Cognitive, behavioral, and psychophysiological treatments of agoraphobia--a comparative outcome investigation. Behav Ther 19: 97-120.
- Shear MK, Pilkonis PA, Cloitre M, Leon AC (1994) Cognitive behavioral treatment compared with nonprescriptive treatment of panic disorder. Arch Gen Psychiatry 51: 395-401.
- Clark DM, Salkovskis PM, Hackmann A, Middleton H, Anastasiades P, et al (1994) A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder. Br J Psychiatry 164: 759-769.
- Sharp DM, Power KG, Simpson RJ, Swanson V, Anstee JA (1997) Global measures of outcome in a controlled comparison of pharmacological and psychological treatment of panic disorder and agoraphobia in primary care. Br J Gen Pract 47: 150-155.
- Telch M, Agras W, Taylor C, Roth W, Gallen C (1985) Combined pharmacological and behavioral treatment for agoraphobia. Behav Res Ther 23: 325-335.
- Dannon PN, Gon-Usishkin M, Gelbert A, Lowengrub K, Grunhaus L (2004) Cognitive behavioral group therapy in panic disorder patients: the efficacy of CBGT versus drug treatment. Ann Clin Psychiatry 16: 41-46.
- Cottraux J, Note ID, Cungi C, Legeron P, Heim F, et al. (1995) A controlled study of cognitive behaviour therapy with buspirone or placebo in panic disorder with agoraphobia. Br J Psychiatry 167: 635-641.
- Stein MB, Ron Norton G, Walker JR, Chartier MJ, Graham R (2000) Do selective serotonin re-uptake inhibitors enhance the efficacy of very brief cognitive behavioral therapy for panic disorder? A pilot study. Psychiatry Res 94: 191-200.
- Mavissakalian M, Michelson L, Dealy RS (1983) Pharmacological treatment of agoraphobia: imipramine versus imipramine with programmed practice. Br J Psychiatry 143: 348-355.
- Wiborg IM, Dahl AA (1996) Does brief dynamic psychotherapy reduce the relapse rate of panic disorder? Arch Gen Psychiatry 53: 689-694.
- Clum GA, Clum GA, Surls R (1993) A meta-analysis of treatments for panic disorder. J Consult Clin Psychol 61: 317-326.
- Cox B, Swinson R, Lee P (1992) Meta-analysis of anxiety disorder treatment studies. J Clin Psychopharmacol 12: 300-301.
- Cox BJ, Endler NS, Lee PS, Swinson RP (1992) A meta-analysis of treatments for panic disorder with agoraphobia: imipramine, alprazolam, and in vivo exposure. J Behav Ther Exp Psychiatry 23: 175-182.
- Fedoroff IC, Taylor S (2001) Psychological and pharmacological treatments of social phobia: a meta-analysis. J Clin Psychopharmacol 21: 311-324.
- Foa EB (2000) Psychosocial treatment of posttraumatic stress disorder. J Clin Psychiatry 61: 43-48.
- Furukawa TA, Watanabe N, Churchill R (2006) Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. Br J Psychiatry 188: 305-312.
- Gould RA, Buckminster S, Pollack MH, Otto MW, Yap L (1997) Cognitive-behavioral and pharmacological treatment for social phobia: A meta-analysis. Clin Psychol Sci Practice 4: 291-306.
- Mattick RP, Andrews G, Hadzi-Pavlovic D, Christensen H (1990) Treatment of panic and agoraphobia. An integrative review. J Nerv Ment Dis 178: 567-576.
- Mitte K (2005) A meta-analysis of the efficacy of psycho- and pharmacotherapy in panic disorder with and without agoraphobia. J Affect Disord 88: 27-45.
- van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, et al. (1997) A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Ment Dis 185: 510-516.
- Westen D, Morrison K (2001) A multidimensional meta-analysis of treatments for depression, panic, and generalized anxiety disorder: an empirical examination of the status of empirically supported therapies. J Consult Clin Psychol 69: 875-899.
- Bandelow B, Seidler-Brandler U, Becker A, Wedekind D, Rüther E (2007) Meta-Analysis of Randomized Controlled Comparisons of Psychopharmacological and Psychological Treatments for Anxiety Disorders. World J Biol Psychiatry 8: 175-187.
- Milrod B, Leon AC, Busch F, Rudden M, Schwalberg M, et al. (2007) A randomized controlled clinical trial of psychoanalytic psychotherapy for panic disorder. Am J Psychiatry 164: 265-272.
- Hoffart A, Martinsen EW (1990) Exposure-based integrated vs. pure psychodynamic treatment of agoraphobic inpatients. Psychotherapy 27: 210-218.
- Teusch L, Bohme H, Gastpar M (1997) The benefit of an insight-oriented and experiential approach on panic and agoraphobia symptoms. Results of a controlled comparison of client-centered therapy alone and in combination with behavioral exposure. Psychother Psychosom 66: 293-301.
- Freire RC, Hallak JE, Crippa JA, Nardi AE (2009) New treatment options for panic disorder: clinical trials from 2000 to 2010. Expert Opin Pharm, McHugh RK, Smits JAJ, Otto MW. Empirically supported treatments for panic disorder. Psychiatr Clin North Am 32:593-610.
- Marazziti D, Carlini M, Dell'Osso L (2012) Treatment strategies of obsessive-compulsive disorder and panic disorder/agoraphobia. Curr Top Med Chem 12(4): 238-253.
- Richerson GB (2004) Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 5: 449-461.
- Javitt DC (2004) Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 9: 984-997.
- Schoepp DD, Wright RA, Levine LR, gaydos B, Potter WZ (2003) LY354740, an mGlu2/3 receptor agonist as a novel approach to Treat Anxiety/Stress. Stress 6:189-197.