Antianxiety medications for the treatment of complex agoraphobia: pharmacological interventions for a behavioral condition

Figures & data

Figure 1 Selection of articles.

Abbreviation: AG, agoraphobia.

Table 1 Number of articles selected for each pharmacological class

Pharmacological class	Articles (n)
TCAs	5
MAOIs	1
BDZs	3
SSRIs	8
NARIs	2
SNRIs	1
Other
Gabapentin (GABAergic anticonvulsant)	1
I nositol (natural isomer of glucose)	1
DCS (partial agonist of the NMDARs)	2
Pagoclone (partial agonist at the GABA-A/BDZ receptor)	1

Abbreviations: BDZ, benzodiazepine; DCS, D-cycloserine; GABA, gamma-aminobutyric acid; MAOI, monoamine oxidase inhibitor; NARI, selective noradrenergic reuptake inhibitor; NMDAR, N-methyl-D-aspartate receptor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Table 2 Systematic analysis of selected studies

Pharmacological class	Reference	Study characteristics	Drug therapy (dosage) in experimental group	Duration of treatment administration	Control group(s)	Outcome measures for AG and/or panic/anxiety	Timing of follow-up	Results
TCAs	Mavissakalian and Perel^Citation45	Double-blind, crossover design Aim: to test the effects of imipramine maintenance therapy in a second-year extension of a previous study	Imipramine (2.25 mg/kg/day)	Maintenance of imipramine therapy (1 year) in patients who had taken imipramine for a year before this study, after stable remission obtained by 6-month imipramine acute-phase treatment	Maintenance of placebo condition (1 year) in patients who had taken placebo for a year before this study, after stable remission obtained by 6-month imipramine acute-phase treatment Placebo substitution (1 year) in patients who had taken imipramine for a year before this study, after stable remission obtained by 6-month imipramine acute-phase treatment	AG subscale of FQ Individualized clinical measure of phobic anxiety and avoidance (9-point scale) Functional in vivo measure of phobic anxiety derived from a behavioral assessment (9-point scale) Number and severity of PAs	1 year	Significant effect of imipramine in maintenance remission
	Mavissakalian and Perel^Citation46	Reanalysis of results from previous studies Aim: to explore relationship between duration of imipramine therapy and relapse	Imipramine (2.25 mg/kg/day)	6 months of imipramine therapy	12–14, 18, or 30 months of imipramine therapy	AG subscale of FQ Individualized clinical measure of phobic anxiety and avoidance (9-point scale) Functional in vivo measure of phobic anxiety derived from a behavioral assessment (9-point scale) Number and severity of PAs	ND	No difference in relapse rate in the different groups Patients who relapsed showed lower severity of agoraphobic symptoms than pretreatment phase, whereas number of PAs measured at relapse and pretreatment phase did not differ
	Marchand et al^Citation47	Double-blind, randomized, placebo-controlled trial	Imipramine (25–200 mg/day) + CBT groups (cognitive and exposure or cognitive or exposure or supportive therapy)	22 weeks, including 4 weeks before beginning of CBT and 18 weeks during CBT	Placebo + CBT treatment groups (cognitive and exposure or cognitive or exposure or supportive therapy)	ACQ MI-A MI-PF	Week 22 3, 6, 12 months post treatment	At week 22, anxiety and agoraphobic symptoms significantly decreased in imipramine and placebo groups without differences between groups; after 12 months no significant differences were detected within and between groups In imipramine group, the proportion of panic-free patients post treatment and at 12 months did not differ among CBT treatments; in placebo group these data were not shown
	Bandelow et al^Citation48	Double-blind, randomized, placebo-controlled trial	Clomipramine (max 112.5 mg/day)	10 weeks	Placebo Exercise (running)	P&A total scores and subscales, including avoidance and anticipatory anxiety subscales BAI FQ	ND	Both exercise and clomipramine led to a significant global improvement in comparison with placebo Overall, clomipramine was significantly more effective and faster in improving anxiety, panic, and phobic symptoms than exercise; however, exercise exerted its effect mainly reducing anticipatory anxiety and panicrelated disability and the decrease of FQ scores in exercise group was higher than placebo group and similar to clomipramine group
	Perna et al^Citation49	Double-blind, randomized, controlled trial	Clomipramine (max 50 mg/day)	30 days	Imipramine (max 50 mg/day) Paroxetine (10 mg/day) Sertraline (25 mg/day) Fluvoxamine (50 mg/day)	PASS FQ	30 days	FQ scores decreased significantly in all treatment groups PASS scores decreased significantly in all but the fluvoxamine treatment group Sertraline was more effective than imipramine in improving PASS scores
MAOIs	Uhlenhuth et al^Citation50	Multicenter, double-blind, randomized, placebocontrolled trial	Moclobemide (75, 150, 300, 600, or 900 mg/day)	8 weeks	Placebo	Agoraphobic avoidance and anticipatory anxiety – CGI 11-point scale of fear and 5-point scale of avoidance for main phobic situations or activities Unexpected and situational PAs (daily diary)	Weeks 1, 2, 3, 4, 6, 8	Moclobemide significantly improved both unexpected and situational PAs (systematic dose-related effect), whereas it did not show significant difference to placebo in fear and phobic avoidance
BDZs	Valença et al^Citation51	Double-blind, randomized, placebo-controlled trial	Clonazepam (2 mg/day)	6 weeks	Placebo	PASS HAM-A CGI	Week 6	Clonazepam showed significant reduction of anticipatory anxiety, phobic avoidance, PAs, global anxiety, and CGI scores compared with placebo
	Valença et al^Citation52	Randomized, placebocontrolled trial	Clonazepam (2 mg/day)	6 weeks	Placebo	GPI for PD Number of PAs HAM-A	Weeks 2, 6	In clonazepam group, by end of week 6 there was a statistically significant remission of PAs and decrease in anxiety
	Katzelnick et al^Citation53	Multicenter, naturalistic, randomized study	Alprazolam (0.25 to >5 mg/day) + SSRIs/SNRIs	8 weeks (including 3- to 4-week taper of alprazolam)	SSRIs/SNRIs alone	Number of PAs HAM-A GPI CGI-I	Weeks 1, 2, 3, 4, 5, 6, 7, 8	Combined therapy showed an earlier onset of effect on anxiety and global improvement measures than SSRIs/SNRls alone PAs decreased significantly at week 8 in both groups without differences between treatment groups at any time point
SSRIs	Uhlenhuth et al^Citation54	Multicenter, double-blind, randomized, placebocontrolled trial	Fluoxetine (one group 10 mg/day; one group 20 mg/day)	10 weeks	Placebo	Index of AG (0-to 8-point scale) Number of spontaneous and situational PAs (daily diary)	Weeks 1, 2, 4, 6, 8, 10	Fluoxetine showed a statistically significant, dose-dependent suppressive effect on spontaneous PAs, whereas there were no significant drug effects on situational PAs A therapeutic effect of fluoxetine on AG was found only at the lower dose
	Kampman et al^Citation55	Double-blind, randomized, placebo-controlled trial Patients unsuccessfully treated with initial manual-guided CBT alone (15 sessions)	Paroxetine (to 40 mg/day) + CBT	8 weeks	Placebo + CBT	ACQ MI-A (total score, MI-A and MI-PF subscales) ADS	Week 8	Patients in paroxetine + CBT condition significantly improved on agoraphobic behaviors and anxiety discomfort Trend showed more panic-free patients in CBT + paroxetine group
	Hendriks et al^Citation56	Randomized, controlled trial Patients aged 60 years and older	Paroxetine (to 40 mg/day)	26 weeks	CBT 14-week WL	ACQ MI-A Proportion of patients free from PAs (panic-free ratio)	Weeks 8, 14 (conclusion CBT/WL), 26 (treated patients only)	Compared with the WL, the 8-and 14-week ACQ and MI-A scores had significantly improved for both the paroxetine and the CBT conditions; the improvements were sustained at the 26-week follow-up without differences between groups The baseline-to-14 weeks panic-free ratio in the paroxetine condition had increased significantly, an improvement that was sustained at week 26 Although not statistically significant, in the CBT condition, the baseline-to-14 weeks ratio had risen and had improved further at follow-up (statistical trend) The panic-free ratio for the WL showed no changes over time
	Wedekind et al^Citation57	Double-blind, randomized, placebo-controlled trial	Paroxetine (10–40 mg/day) + relaxation training or aerobic exercise	10 weeks	Placebo + relaxation training or aerobic exercise	P&A HAM-A BAI CGI	Weeks 1, 2, 4, 6, 8, 10	P&A, CGI, and BAI scores decreased significantly in all treatment groups over time, but paroxetine-treated patients were significantly more improved than placebotreated patients On the CGI, patients in the exercise groups (+ paroxetine or placebo) had a trend toward better improvement compared with relaxation HAM-A scores decreased significantly, without differences, in all treatment groups
	Bandelow et al^Citation58	Double-blind, randomized, controlled trial	Sertraline (50–150 mg/day)	12 weeks	Paroxetine (40–60 mg/day)	P&A Frequency and intensity of PAs and anticipatory anxiety (panic diary)	Weeks 1, 2, 4, 6, 8, 12	Sertraline and paroxetine showed equivalent efficacy Sertraline was significantly better tolerated and was associated with significantly less clinical worsening during taper than paroxetine
	Stahl et al^Citation59	Multicenter, double-blind, randomized, placebocontrolled trial	Escitalopram (5 mg/day ÷ max 20 mg/day) Citalopram (10 mg/day ÷ max 40 mg/day)	10 weeks	Placebo	P&A Anticipatory anxiety and number of PAs (from PASS score) CGI-phobic avoidance HAM-A	Weeks 1, 2, 4, 6, 8, 10	At the endpoint, escitalopram (vs placebo) had significant effect on anticipatory anxiety and HAM-A scores Both escitalopram and citalopram had significant effect on number of PAs and CGI-phobic avoidance score compared with placebo, without significant differences between them
	Bandelow et al^Citation60	Double-blind, randomized, placebo-controlled trial	Escitalopram (5 mg/day ÷ max 20 mg/day) Citalopram (10 mg/day ÷ max 40 mg/day)	10 weeks	Placebo	P&A (agoraphobic avoidance behavior, anticipatory anxiety and PAs subscales)	Week 10	Compared with placebo, escitalopram had significant effect on agoraphobic avoidance behavior and anticipatory anxiety subscales and citalopram on anticipatory anxiety subscale Both drugs, compared with placebo, significantly decreased the number of PAs, without differences between them
	Perna et al^Citation61	Single-blind, randomized, controlled trial	Citalopram (10 mg/day ÷ max 50 mg/day)	ND	Paroxetine (10 mg/day ÷ max 50 mg/day)	PASS FQ	Days 7, 60	Both drugs significantly improved panic and phobic symptomatology A trend of higher efficacy of paroxetine in reducing PAs was found
NARIs	Versiani et al^Citation62	Double-blind, randomized, placebo-controlled trial	Reboxetine (2–8 mg/day)	8 weeks	Placebo	SPAAS and number of PAs	Weeks 1, 2, 3, 4, 5, 6, 7, 8	At last assessment, anticipatory anxiety, AG, and PAs significantly decreased in reboxetine group
	Bertani et al^Citation63	Single-blind, randomized, controlled trial	Reboxetine (2–8 mg/day)	90 days	Paroxetine (10 mg/day ÷ 40 mg/day)	PASS FQ	Day 90	A greater effect of paroxetine than reboxetine on PAs was found, while no differences for anticipatory anxiety and phobic avoidance were found
SNRIs	Pollack et al^Citation64	Double-blind, randomized, controlled trial	Venlafaxine extended release (75 or 150 mg/day)	12 weeks	Placebo Paroxetine (40 mg/day)	PAAS (anticipatory anxiety and PAs subscales) Phobic fear and avoidance of phobia scale HAM-A PDSS	Weeks 1, 2, 3, 4, 6, 8, 10, 12	Venlafaxine and paroxetine showed significant effects on all measures, compared with placebo, without differences between them
Other	Pande et al^Citation65	Double-blind, randomized, placebo-controlled trial	Gabapentin (600–3600 mg/day)	8 weeks	Placebo	P&A total score HAM-A	Week 8	No significant reduction of anxiety and panic symptoms in gabapentin group compared with placebo A trend of higher efficacy in a subgroup of more severely ill patients was found
	Sandford et al^Citation66	Double-blind, randomized, placebo-controlled, crossover design	Pagoclone (0.3 mg/day)	2 weeks	Placebo	HAM-A Frequency of PAs (diary)	Weeks 1, 2, 3, 4, 5, 6	Statistical trend of decrease in the number of PAs within pagoclone group was found, but no differences were found when compared with placebo
	Otto et al^Citation67	Randomized, doubleblind, placebo-controlled augmentation trial	DCS (50 mg) + CBT (five sessions)	Administration 1 hour before CBT sessions 3–5	Placebo (50 mg) + CBT (five sessions)	PDSS CGI-S for PD (global score, number and frequency of PAs, anticipatory anxiety, phobic avoidance, impairment of function)	1 week (post treatment) and 1 month (follow-up) following cessation of treatment	DCS had an augmentation effect on CBT efficacy PDSS and CGI-S decreased significantly in DCS group (vs placebo) post treatment, whereas no significant differences between groups were shown in follow-up
	Siegmund et al^Citation68	Double-blind, randomized, placebo-controlled trial	DCS (50 mg) + CBT	Administration once before CBT exposure sessions (only weeks 2, 3, 4)	Placebo + CBT	P&A BAI HAM-A	After 11 CBT sessions and at 1 and 5 months after end of CBT	Both groups profited considerably from therapy and DCS did not significantly improve the outcome There was a statistical trend in the more severely ill patients that DCS accelerated symptom reduction post therapy
	Palatnik^Citation69	Double-blind, randomized, controlled, crossover design	Inositol (18 g/day)	4 weeks	Fluvoxamine (150 mg/day)	FQ Number of PAs (diary) HAM-A	Weeks 3, 4, 5, 6, 8, 9	Similar improvement in both groups on all measures, except for some superiority of inositol in reducing PAs

Abbreviations: ACQ, Agoraphobic Cognition Questionnaire; ADS, Anxiety Discomfort Scale; AG, agoraphobia; BAI, Beck Anxiety Inventory; BDZ, benzodiazepine; CBT, cognitive behavioral therapy; CGI, Clinical Global Impression; CGI-I, Clinical Global Impression of Improvement; CGI-S, Clinical Global Impression of Severity; DCS, D-cycloserine; FQ, Fear Questionnaire; GPI, Global Patient’s Impression scale; HAM-A, Hamilton Anxiety Rating Scale; MAOI, monoamine oxidase inhibitor; max, maximum; MI-A, Mobility Inventory for Agoraphobia; MI-PF, Mobility Inventory for Panic Frequency; NARI, selective noradrenergic reuptake inhibitor; ND, no data reported; P&A, Panic and Agoraphobia Scale; PA, panic attack; PAAS, Panic and Anticipatory Anxiety Scale; PASS, Panic Attack Symptoms Scale; PD, panic disorder; PDSS, Panic Disorder Severity Scale; SNRI, serotonin-norepinephrine reuptake inhibitor; SPAAS, Sheehan Panic Attack and Anxiety Scale; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; vs, versus; WL, waiting list.

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