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Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database
Journal of Psychiatric Research 90 (2017) 60e66
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Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database Delphine Abadie a, *, Anaïs Essilini a, Virginie Fulda b, Aurore Gouraud c, €lle Micallef e, François Montastruc a, Jean Louis Montastruc a lissa Ye le he -Okouma d, Joe Me Department of Medical and Clinical Pharmacology, Toulouse University Hospital, Faculty of Medicine, 37 all ees Jules Guesde, 31000 Toulouse, France ^pital Europ Regional Pharmacovigilance Center, Ho een Georges Pompidou, 20-40 rue Leblanc, 75015 Paris, France c Regional Pharmacovigilance Center, Hospices Civils de Lyon, 162 avenue Lacassagne, 69424 Lyon, France d ^pitaux de Nancy, 29 Avenue du Mar Regional Pharmacovigilance Center, Ho echal de Lattre de Tassigny, 54035 Nancy, France e ^pital Sainte-Marguerite AP-HM, 270 boulevard de SaintRegional Pharmacovigilance Center, Department of Medical and Clinical Pharmacology, Ho Marguerite, 13009 Marseille, France a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 June 2016 Received in revised form 3 February 2017 Accepted 8 February 2017
Background: The potential role of drugs in the onset of panic attacks (PAs) is poorly understood. Aim: The objective of our study was to characterize drug-induced PAs. Method: We performed an analysis of PAs registered in the French pharmacovigilance database between 01/01/1985 and 05/11/2014. Results: Among the 163 recorded cases, 136 (83.4%) were directly related to drugs, mainly antidepressants (11.3%, mainly serotonin reuptake inhibitors), mefloquine (7.2%), isotretinoin (5.2%), rimonabant (3.6%) and corticosteroids (4.7%). PAs are labelled in the Summary of Product Characteristics (SmPC) for a minority (8.6%) of these drugs. In 31.4% of these cases, withdrawal of the suspected drug was performed more than a week after the onset of PAs. PAs could also be secondary to another adverse drug reaction (ADR; n ¼ 14, 8.6%), mainly an allergy to antineoplastic or immunomodulating agents. In 13 cases (8.0%), PAs occurred during a drug-withdrawal syndrome, mainly after benzodiazepines or opioids. Most cases (73%) involved patients without any previous psychiatric disorder. Conclusion: This is the first pharmacoepidemiological study about iatrogenic PAs. Beside antidepressants, the most often encountered drugs are not indicated for psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians, especially since PAs are generally not labelled in SmPCs of the suspected drugs. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Panic attack Adverse drug reaction Pharmacovigilance database
1. Introduction A panic attack (PA) is an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, with occurrence of 4 or more of cardiovascular (palpitations …), autonomic (sweating …), pulmonary (sensation of smothering …), neurological (trembling …), gastrointestinal (nausea …) or psychological (derealization …) symptoms (American Psychiatric Association, 2016).
* Corresponding author. Present address: Department of Medical and Clinical -Salpe ^trie re Hospital, 47-83 Pharmacology, Regional Pharmacovigilance Center, Pitie ^pital, 75013 Paris, France. Boulevard de l'Ho E-mail address: [email protected] (D. Abadie). http://dx.doi.org/10.1016/j.jpsychires.2017.02.008 0022-3956/© 2017 Elsevier Ltd. All rights reserved.
PAs occur across all cultures and nations and are common in the general population (Kessler et al., 2006; Yates, 2009). According to an American nationwide study, lifetime rates of PA prevalence are elevated, with almost a third of patients reporting at least one PA during their life (Kessler et al., 2006). Recurrent unexpected PAs can lead to panic disorder (PD), which is characterized by longer than 1 month of: (1) subsequent persistent worry about having another attack or consequences of the attack, or (2) significant maladaptive behavioral changes related to the attack (American Psychiatric Association, 2016). Several factors could contribute to the origin of PAs, including genetic (genes conferring vulnerability), psychopathological (cognitive distorsions and misinterpretations of somatic
D. Abadie et al. / Journal of Psychiatric Research 90 (2017) 60e66
experiences) and neurobiological ones (Dresler et al., 2013; Gorman et al., 2000; Millan, 2003; Roy-Byrne et al., 2006). In the widely acknowledged revised version of their 1989 neuroanatomical hypothesis for PD, Gorman suggested that panic originates in an abnormally sensitive “fear network” in the brain, that is centered in the amygdala which stands as the central point for dissemination of information and that coordinates fear responses (Gorman et al., 2000, Fig. 1). According to this model, the sensory input for the conditioned stimulus runs through the anterior thalamus to the amygdala, which in turn stimulates: (i) the parabrachial nucleus, producing an increase in respiratory rate; (ii) the lateral nucleus of the hypothalamus, activating the sympathetic nervous system and causing sympathetic discharge; (iii) the locus ceruleus, resulting in an increase in noradrenaline (NA) release and contributing to increases in blood pressure, heart rate, and the behavioral fear response; and (iv) the paraventricular nucleus of the hypothalamus, rising the release of adrenocorticoids (Gorman et al., 2000, Fig. 1). Consistent with Gorman's hypothesis, neuroimaging studies have subsequently reported in patients with PD an increased reactivity of the amygdala with volume reduction and structural deficit (Kim et al., 2012). Modern neuroimaging techniques since 2000 have also pointed to (i) the involvement of other cortical areas and other brain circuitry (e.g. the insula and anterior cingulate cortex) (Dresler et al., 2013; Pannekoek et al., 2013) and (ii) other neurochemical alterations within the fear network such as altered GABAergic [particularly in frontal and cingulate cortex (Long et al., 2013)] and serotonergic transmission [particularly in the raphe nuclei (Nash et al., 2008; Neumeister et al., 2004)]. Currently, the potential role of drugs in the onset of PAs is poorly understood. No pharmacoepidemiological study has been performed to evaluate, at a population level, the characteristics of drug-induced PAs. Consequently, more information would be required for a better understanding of iatrogenic PAs in routine clinical practice. Our objective was to analyze characteristics of PAs registered in the French PharmacoVigilance Database (FPVD), especially involved drugs.
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2. Material and methods 2.1. Data source The French Pharmacovigilance system was first established in 1973 and consists of a network of 31 regional centers (Moore et al., 1995; Vial, 2016). The FPVD was subsequently established in 1985 to record any Adverse Drug Reaction (ADR) spontaneously notified by health professionals. Reporting ADRs to the French regional centers has been mandatory for any drug prescriber (physician, dentist, or midwife) or pharmacist in France since 1995 (Moore et al., 1995; Vial, 2016). Other healthcare professionals and more recently patients (decree of June 10th, 2011) can also report ADRs. In 2016, more than 623,000 reports of ADRs are registered in this database. For each report, information about patient (age, gender, past medical history), ADR [type (coded according to the Medical Dictionary for Drug Regulatory Activities MedDRA (Brown et al., 1999), date of onset, duration and evolution], and drug exposure [name, intake dates, doses] are recorded. A detailed summary of clinical description is added at the end of each pharmacovigilance case report. For all reports, a causality assessment (“imputability” or “imputation”) is done for each drug using the French Pharmacovigilance System's method (Miremont-Salame et al., 2016). If causality is found between the drug and the occurrence of the ADR, drugs are defined as “suspected” and if not, they are defined as “associated” (non-suspected) (Miremont-Salame et al., 2016). 2.2. Data analysis We performed an analysis of spontaneous reports of PAs registered in the FPVD between 01/01/1985 and 05/11/2014 under the MedDRA terms “Panic attacks and disorders” (High Level Term) or “Anxiety attack” (Low Level Term). Clinical symptomatology of each reported case was thoroughly examined by 2 pharmacovigilance specialists (DA, JLM) and 1 psychopharmacologist (FM). Cases corresponding to another medical diagnosis or those without sufficient data were excluded. For each case, we systematically recorded variables related to the patient (age, gender and medical history),
Fig. 1. Neuroanatomical pathways potentially involved in panic attacks according to Gorman's hypothesis (Gorman et al, 2000).
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D. Abadie et al. / Journal of Psychiatric Research 90 (2017) 60e66
PA (date of onset, “seriousness”, clinical characteristics, management and outcome) and suspected drugs (name, intake dates, doses). A “serious” ADR is defined as any untoward medical occurrence that at any dose results in death, requires hospital admission or prolongation of existing hospital stay, results in persistent or significant disability/incapacity or is life threatening (Edwards and Aronson, 2000).
agents. The second most often encountered ADRs inducing PAs were psychiatric ones (n ¼ 5, 36%): hallucinations (zolpidem, oxycodone) or insomnia (mefloquine, morphine). In the 2 last cases, PAs occurred in the context of nausea and neurological disorders (dizziness or coordination disorder) induced by risperidone or ropinirole. Anxiety is labelled in the SmPC only for mefloquine and risperidone, and PA only for mefloquine (European Medicines Agency, 2016).
3. Results 3.1. General characteristics of cases Of the 555,813 notifications recorded in the FPVD, 189 (0.03%) were reported as a PA, among which 163 (86.2%) were analyzed. Average age of patients was 42.1 ± 18.7 years, mostly adults (80.3% between 15 and 65 years, including 46.0% between 18 and 45 years). Children (under 15 years of age: 5.5%) and elderly patients (more than 65 years of age: 12.9%) were in minority. Reports concerned mainly females (n ¼ 104; 63.8%). A medical history of psychiatric disorder was reported for 27.0% of patients (mostly a depressive disorder: 15.3%). Very few patients (4.3%) had a past medical history of anxiety (including those with previous PAs). A minority of cases were “serious” (n ¼ 27, 16.6%), including 25 hospital admissions or prolongations of existing hospital stay and 2 significant disabilities/incapacities.
3.3.3. PAs occurring in the context of a withdrawal syndrome (n ¼ 13, 8.0%) Mean age of patients was 41.4 years (±10.7), majority females (n ¼ 10, 76.9%). The most often involved drugs were benzodiazepines (n ¼ 5, mainly prazepam) and opioid analgesics (n ¼ 5, mainly tramadol). 3.4. Management and evolution of cases (Table 2) In the group of PAs directly induced by drugs, the suspected drug was generally discontinued after PAs onset. Although the drug was frequently stopped rapidly (the day of the PA onset), in almost a third of cases, it took more than a week before a practitioner finally discontinued it. On the whole, around 1 out of 3 patients needed a pharmacological treatment for PAs, mainly an anxiolytic alone. Even if most of patients suffered from repeated PAs, the outcome was generally favorable.
3.2. General repartition of suspected drugs (Table 1) 3.5. Focus on « serious » cases A total of 194 drugs was suspected (mean of 1.2 suspected drugs per report). The most often encountered drugs were antidepressants [mainly serotonin reuptake inhibitors (SRIs)], followed by mefloquine, isotretinoin, rimonabant and corticosteroids. 3.3. Etiological groups of PAs A detailed analysis of case reports allowed us to distinguish 3 etiological groups of PAs: 1) PAs directly related to drugs [i.e. PAs occurring during treatment with the suspected drug], 2) PAs secondary to another ADR [i.e. PAs occurring during treatment with the suspected drug and due to another ADR induced by this drug] and 3) PAs occurring in a context of a drug-withdrawal syndrome. 3.3.1. PAs directly induced by drugs (n ¼ 136, 83.4%) Mean age of patients was 42.5 years (±19.4), mainly females (n ¼ 82, 60.3%). Most of time (n ¼ 59, 46%), PAs occurred during the hours immediately following introduction of the suspected drug. The most often involved drugs were antidepressants [n ¼ 19, mostly SRIs and especially paroxetine (n ¼ 5)] and the great majority (93%) of related PAs occurred during the first week of treatment. The most often encountered drugs following antidepressants were (n 3): mefloquine (n ¼ 13), isotretinoin (n ¼ 9) rimonabant (n ¼ 7), corticosteroids [prednisone (n ¼ 3), budesonide (n ¼ 3)], pregabaline (n ¼ 4) and methylphenidate (n ¼ 3). PAs are labelled in the Summary of Product Characteristics (SmPC) for only 8.6% of the 105 suspected drugs (e.g. SRIs, mefloquine or rimonabant) (European Medicines Agency, 2016). Most frequently (91.4%), PAs are not labelled (e.g. isotretinoin, corticosteroids or methylphenidate). Anxiety is labelled for about half (49.5%) of the suspected drugs (e.g. SRIs, mefloquine, rimonabant or isotretinoin) (European Medicines Agency, 2016). 3.3.2. PAs secondary to another ADR (n ¼ 14, 8.6%) Mean age of patients was 39.4 years (±18.6), mainly females (n ¼ 12, 86%). These PAs were mainly (n ¼ 7, 50%) the consequence of an allergic reaction to antineoplastic or immunomodulating
3.5.1. Hospital admissions or prolongations of existing hospital stay (n ¼ 25) Mean age of patients was 42.1 ± 21.3 years, mostly females (n ¼ 13). In the vast majority of the corresponding cases (n ¼ 21), the PA was directly induced by drugs [most often involved drugs: SRIs (n ¼ 2), mefloquine (n ¼ 2) or rimonabant (n ¼ 2)], in 3 cases the PA occurred in the context of a withdrawal syndrome (bromazepam, methadone or morphine), and in the last case, the PA was due to another ADR (allergic reaction due to paclitaxel). Most of the patients (n ¼ 22) fully recovered, one recovered with sekelae (persistent anxiety after isotretinoin treatment) and 2 did not recovered (persistent PAs after mefloquine or varenicline treatment). 3.5.2. Disabilities/incapacities (n ¼ 2) Two young women (18 and 19 years-old) presented significant and severe disability/incapacity due to persistent PAs (isotretinoin or adalimumab). 4. Discussion As far as we know, this is the first published study that investigates at a population level and through a large pharmacovigilance database the characteristics of iatrogenic PAs. Our results show that, in real clinical practice, various drugs can induce a PA, the first ones being antidepressants and especially SRIs, followed by the widely used antimalarial drug mefloquine, the anti-acne drug isotretinoin, rimonabant, a weight loss drug, and corticosteroids. Our study suffers from some compulsory methodological drawbacks, as with all other studies using a pharmacovigilance database [underreporting, biases in reporting, indication bias, lack of the total number of treated patients (Thiessard et al., 2005; Weber, 1984)]. Nonetheless, it should be noted that our aim was not to describe exhaustively all cases of iatrogenic PAs occurring in France, but rather to review the drugs involved in reports of PAs. Moreover, despite these limitations, compared with previous
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Table 1 Drugs involved in Panic Attacks (PAs) registered in the French Pharmacovigilance database according to Anatomical Therapeutic Classificationa. Drug
n
(%)
A Alimentary tract and metabolism A08 Antiobesity preparations A08AX Other antiobesity drugs
15 8 7
(7.7) (4.1) (3.6)
rimonabant
7
(3.6)
D Dermatologicals D10 Anti-acne preparations D10BA Retinoids for treatment of acne
12 10 10
(6.2) (5.2) (5.2)
isotretinoin
10
(5.2)
H Systemic hormonal preparations H02 Corticosteroids for systemic use H02AB Glucocorticoids
7 6 6
(3.6) (3.1) (3.1)
prednisone
3
(1.6)
N Nervous system N03 Antiepileptics N03AX Other antiepileptics
79 8 7
(40.7) (4.1) (3.6)
pregabalin
5
(2.6)
N06 Psychoanaleptics N06A Antidepressants N06AB Selective serotonin reuptake inhibitors
28 22 12
(14.4) (11.3) (6.2)
paroxetine
6
(3.1)
N06AX Other antidepressants
10
(5.2)
mianserin
4
(2.1)
N06B Psychostimulants N06BA Centrally acting sympathomimetics
4 4
(2.1) (2.1)
methylphenidate
3
(1.6)
P Antiparasitic products P01 Antiprotozoals P01B Antimalarials P01BC Methanolquinolines
15 15 15 14
(7.7) (7.7) (7.7) (7.2)
mefloquine
14
(7.2)
R Respiratory system R03 Drugs for obstructive airway diseases R03BA Glucocorticoids
14 6 3
(7.2) (3.1) (1.6)
budesonide
3
(1.6)
Total
194
(100.0)
a b c
Time to PA onsetb
Anxiety labelledc
PA labelledc
32
Yes
Yes
51
Yes
No
1
No
No
2
Yes
Yes
0,5
Yes
Yes
2
No
Yes
3
Yes
No
2
Yes
Yes
11
Yes
No
Data not shown if less than 3 patients were exposed to the drug. Median, in days. Summary of Products Characteristics.
publications about iatrogenic PAs (isolated case reports), our systematic analysis of French notifications is original from a methodological point of view. It offers a picture more in line with usual medical practice and therefore constitutes a unique approach to improve our knowledge on circumstances of occurrence of this relatively unknown (and rare) ADR. In terms of age and gender, our patients were comparable to those described in the literature as having a high risk of suffering from PAs. Effectively, female gender appears to constitute a significant risk factor for PAs (Kessler et al., 2006). Moreover, PAs appear to be more likely in those in the 18-to-45 year age group and lower rates are typically seen in persons age 65 and older, which may reflect a tendency for PA to abate over time (Kessler et al., 2006; Yates, 2009). It is only for a minority of patients that the first lifetime PA appears before fifteen years old (Kessler et al., 2006). We surprisingly found a low rate of patients with a past medical history of psychiatric disorder (27%), especially for anxiety and PA (4%). In contrast, epidemiological studies have reported, in patients with at least 1 lifetime PA, a higher percentage (72%) of comorbidity
with another psychiatric disorder (Kessler et al., 2006). Thus, our population is clearly different regarding psychiatric history from that who usually experiences typical PAs. To our opinion, the iatrogenic hypothesis seems highly probable to explain why these patients without preexisting history of anxiety begin one day to develop their first PA, given (i) the temporal coexistence with the culprit drug exposure and (ii) the underlying pharmacological plausibility (see below). We could also assume that without exposure to the culprit drug, most of our patients might perhaps have never experienced any PA. Few studies have suggested that ADRs could have a psychological impact on patients' lives (Butt et al., 2011). To our knowledge, our study is the first to show that, in routine clinical practice, stress induced by an ADR can trigger true PA. As this point was not previously reported in the literature, it constitutes one of the major findings of the present work. Results of epidemiological studies tend to illustrate that anxiety disorders in general are insidious and characterized by a chronic clinical course with low rates of recovery and relatively high probability of recurrence (Hendriks et al., 2013). The high rate of
64
D. Abadie et al. / Journal of Psychiatric Research 90 (2017) 60e66 Table 2 Management and evolution of panic attacks registered in the French pharmacovigilance database between 1985 and 2014. n (%) Discontinuation of the suspected drug (n ¼ 152)a No Yes Rechallenge Positive rechallenge
7 (4.6) 145 (95.4) 25 (17.2) 17 (68.0)
Time to discontinuation of the suspected drug (n ¼ 118, in days)a <1 44 (37.3) [1e7] 37 (31.4) >7 37 (31.4) Hospitalization (n ¼ 163) No Yes
138 (84.7) 25 (15.3)
Pharmacological treatment (n ¼ 145) No Yesb 1/Anxiolytic only Benzodiazepine H1 antagonist 2/Benzodiazepine þ antidepressant 3/Antidepressant only
97 (66.9) 48 (33.1) 24 (50.0) 15 (31.3) 6 (12.5) 7 (14.6) 5 (10.4)
Psychiatric follow up (n ¼ 140) No Yes
121 (86.4) 19 (13.6)
Number of panic attacks (n ¼ 137) 1 Multiple
41 (29.9) 96 (70.1)
Evolution (n ¼ 152) Recovered Not recovered Recovered with sekelaec
125 (82.2) 25 (16.4) 2 (1.3)
a
Panic attacks directly induced by drugs. Data not shown if less than 5 patients were exposed to the pharmacological treatment. c Residual anxiety. b
recovery observed in our study (82.2%) could be due to the disappearance of the PA-triggering factor, since in most cases the culprit drug was stopped. On the contrary, predisposing/triggering factors for typical PAs (e.g. genetic predisposition, stressfull living conditions) are not often easily identifiable or removable. Another point to consider is due to the fact that our population was medically followed-up, since the great majority of culprit drugs need a medical prescription in France. Conversely, for many patients with anxiety disorders, it may last months, even years until they are referred to a specialist. In terms of PA management, we observed that, in about a third of cases, cessation of the suspected drug was performed more than a week after the PA onset. This high proportion of cases with delayed management reveals that there is still work to be done to sensitize physicians to the fact that PAs can be drug-induced. This is all the more important since PAs are generally not labelled in SmPCs of the suspected drugs. From a practical point of view, our results indicate that a systematic anamnesis about drugs should be involved in each etiological research of PA. The present work also allows discussion of several interesting points from a pharmacological point of view. Firstly, we found that a large variety of drugs with distinct mechanisms of action are capable of producing PA in susceptible patients. According to the Gorman's fear network model and subsequent discoveries on
neurochemical alterations within this fear network, the heterogeneity of culprit drugs could be explained by (i) the several neurotransmitters involved in the underlying mechanisms of PA, with a high degree of interconnectivity (Dresler et al., 2013; Gorman et al., 2000; Millan, 2003; Roy-Byrne et al., 2006) and (ii) the fact that a drug that causes PA does not only interact with a specific cerebral area but, rather, activates the entire fear network (Gorman et al., 2000). Antidepressants and especially SRIs have been used for the treatment of several anxiety disorders, including PD (Lai and Wu, 2013; Sheehan et al., 2005; Simon et al., 2004). However, antidepressants only exert their effect after 3e4 weeks of repeated administration, and during the initial phase of treatment, they can paradoxically produce an initial exacerbation of anxiety symptoms, especially in PD (Akimova et al., 2009; Nascimento et al., 2014). Consistently with these data, in our study, the great majority of antidepressant-induced PAs occurred during the first week of treatment. This phenomenon could be due to an oversensitivity of key serotonin postsynaptic receptors (Coplan et al., 1992), which could be reversed to its opposite in synapses regulating anxiety as the result of adaptive mechanisms, such as down regulation of post synaptic receptors (Stahl, 1998). It has been shown in preclinical models that elevation in anxiety acutely after SRIs can be blocked by antagonists of 5HT-2 receptors (Bagdy et al., 2001). The opposite effects of SRIs between acute and subchronic administrations are also illustrated by neuroimaging findings showing that acute SRI administration to man enhances amygdala reactivity (Bigos et al., 2008) whilst subchronic treatment reduces it (Harmer et al., 2006). The accumulated preclinical and clinical (several case reports, observational studies and randomized controlled trials) evidence supports mefloquine, a widely used antimalarial drug, being psychoactive and neurotoxic (Schneider et al., 2013). Mefloquine has been associated with a variety of neuropsychiatric reactions such as PAs (European Medicines Agency, 2016; Meier et al., 2004). The underlying mechanism is not clear, but mefloquine is highly lipophilic and may accumulate in the limbic system (which includes the amygdala) relative to other areas in the brain, where it acts to disrupt a form of cellular electrical communication that is essential for coordinated inhibitory control (Ritchie et al., 2013). In particular, available evidence suggests that mefloquine critically affects synchrony of GABAergic neurons through a blockade of membrane channels (connexins and KATP channels)(Quinn, 2015). Isotretinoin is a retinoid derivative from the essential nutrient vitamin A, often used in adolescents with severe acne. Even if its psychiatric risk has been a controversial topic for many years (Strahan and Raimer, 2006), the available literature data strongly suggest a link with depression (Ludot et al., 2015). The risk of anxiety has been less investigated, but isolated case reports of isotretinoin-related PAs have been published (Poblete et al., 2006). Psychiatric ADRs have been described in patients exposed to high doses of vitamin A (Restak, 1972). It has been shown that, in the hypothalamus, endogenous retinoic acid regulates some genes involved in corticotrophin-releasing factor (CRF) synthesis, a key regulating factor in the HPA axis, a central component in the response to stress (Abelson et al., 1996; Bremner et al., 2012; Mathew et al., 2008) which is dysregulated in patients with PD (Abelson et al., 2007). Exposure of cells to isotretinoin, which is isomerized in tissue to the active all-trans retinoic acid, results in inappropriate gene transcription which may contribute to HPA axis hyperactivity (Bremner et al., 2012). Moreover, a neuroimaging study showed that isotretinoin treatment was associated with decreased brain metabolism in the prefrontal cortex (Bremner et al., 2005), and a neurocognitive deficit in this area could be involved in an inappropriate activation of the “fear network” via misguided excitatory input to the amygdala (Gorman et al., 2000).
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Rimonabant is a selective cannabinoid type-1 (CB1) receptor antagonist used as an adjunct for the treatment of obesity, until its withdrawal in Europe in 2009 after concern about psychiatric ADRs (serious depressive states and suicides) (Sweetman, 2011). Anxiety occurs commonly with this drug and can lead to PAs (European Medicines Agency, 2016). Endocannabinoid system is known to play a key role in mental processes, and, as a function of personality and the precise circumstances of testing, cannabinoids have been found to either relieve or induce anxiety in man (Millan, 2003). Notwithstanding these complex effects, CB1 receptor antagonists generally provoke an increase in anxiety in rodents (Millan, 2003). This could be explained by the fact that cannabinoids modulate the release of several neurotransmitters implicated in anxious states (such as glutamate or NA) (Millan, 2003). The psychostimulant effects of glucocorticoïds (GCs), the most commonly prescribed anti-inflammatory/immunosuppressant drugs worldwide, are well known. GCs can induce a large spectrum of psychopathological disturbances, ranging from agitation to severe mental disorders such as psychosis (Judd et al., 2014). Few case reports have also implicated GCs in causing PAs (Iskandar et al., nyi et al., 1988). A recent cohort study found a significant 2011; Pere increase of PD incidence during the first 3 months of a course of oral GC treatment (Fardet et al., 2012). High levels of cortisol, the main endogenous glucocorticoid, inhibit brain-derived neurotrophic factor, which is important for maintaining neural architecture in key brain regions such as the hippocampus and prefrontal cortex (Duman and Monteggia, 2006). Neuroimaging studies have shown functional changes in several brain regions after acute or chronic GCs treatment (Judd et al., 2014), including atrophy of the right amygdala (Brown et al., 2008), which is thought to predispose to PD (Kim et al., 2012). Methylphenidate, a piperidine derivative structurally related to amphetamine, is used in attention-deficit hyperactivity disorders and narcolepsy. Amphetamines appear to exert most of their effects in the central nervous system by releasing biogenic amines (mostly noradrenaline and dopamine) from their storage sites in nerve terminals and by blocking their reuptake (Brunton et al., 2011). Some studies revealed that chronic use of methylphenidate was associated with neurochemical alterations of the amygdala, including oxidative stress and inflammation (Motaghinejad et al., 2016). A recent neuroimaging study showed multiple effects of methylphenidate on brain functions, including an increase of thalamic connectivity to the hippocampus and amygdala, which may speak to its alerting-enhancing effects (Farr et al., 2014). In contrast, for one drug, PAs cannot be explained by a simple pharmacological mechanism. Pregabalin is a GABA analog used worldwide as an antiepileptic but also in the treatment of generalised anxiety disorder (Frampton, 2014). Its precise mechanism of action is still discussed [decrease in calcium-dependent release of neurotransmitters implicated in anxiety disorders, including NA (Dooley et al., 2000)]. It is somewhat surprising to observe PAs with this drug. Our cases are all the more interesting in that (i) pregabalin was always prescribed for pain (and not for anxiety), (ii) none of the patients had a past medical history of anxiety or PAs and (iii) chronology was suggestive since, in each case, evolution was favorable after pregabalin discontinuation. Even if PAs are labelled in pregabalin SMPc (European Medicines Agency, 2016), literature data rather suggest that pregabalin-induced PAs or anxiety only occur in the context of a withdrawal syndrome. In conclusion, this is the first study about drug-induced PAs based on a large pharmacovigilance database. Our results highlight that various drugs induce PAs in routine clinical practice, the first ones being antidepressants, especially SRIs. Interestingly, the most often encountered drugs following antidepressants (mefloquine, isotretinoin, rimonabant and corticosteroids) are not indicated for
65
psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians. This is all the more important since PAs are generally not labelled in SmPCs of the suspected drugs. Role of funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Contributors DA, AE, FM and JLM participated in the study design, planning, and analyses of cases. DA and AE managed the literature searches and interpretation of the data. FM and JLM took part in the interpretation of the data. DA wrote the first draft of the manuscript. FM and JLM critically revised the manuscript for important intellectual content. All authors contributed to and have approved the final manuscript. Conflict of interest None to declare. Abbreviations ADR CB1 CRF FPVD GC HPA 5HT MedDRA NA PA PD SmPC SRI
adverse drug reaction cannabinoid type-1 corticotrophin-releasing factor French pharmacovigilance database glucocorticoïd hypothalamus/pituitary/adrenal 5-hydroxytryptamine medical dictionary for regulatory activities noradrenaline panic attack panic disorder Summary of Product Characteristics serotonin reuptake inhibitor
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Millan, M.J., 2003. The neurobiology and control of anxious states. Prog. Neurobiol. 70, 83e244. , G., The ophile, H., Haramburu, F., Be gaud, B., 2016. Causality Miremont-Salame assessment in pharmacovigilance: the French method and its successive updates. Therapie 71, 179e186. Moore, N., Noblet, C., Kreft-Jais, C., Lagier, G., Ollagnier, M., Imbs, J.L., 1995. [French pharmacovigilance database system: examples of utilisation]. Therapie 50, 557e562. Motaghinejad, M., Motevalian, M., Shabab, B., 2016. Neuroprotective effects of various doses of topiramate against methylphenidate induced oxidative stress and inflammation in rat isolated hippocampus. Clin. Exp. Pharmacol. Physiol. 43, 360e371. Nascimento, J.O.G., Kikuchi, L.S., De Bortoli, V.C., Zangrossi, H., Viana, M.B., 2014. Dorsomedial hypothalamus serotonin 1A receptors mediate a panic-related response in the elevated T-maze. Brain Res. Bull. 109, 39e45. Nash, J.R., Sargent, P.A., Rabiner, E.A., Hood, S.D., Argyropoulos, S.V., Potokar, J.P., Grasby, P.M., Nutt, D.J., 2008. Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br. J. Psychiatry 193, 229e234. Neumeister, A., Bain, E., Nugent, A.C., Carson, R.E., Bonne, O., Luckenbaugh, D.A., Eckelman, W., Herscovitch, P., Charney, D.S., Drevets, W.C., 2004. Reduced serotonin type 1A receptor binding in panic disorder. J. Neurosci. 24, 589e591. Pannekoek, J.N., Van der Werff, S.J.A., Stein, D.J., Van der Wee, N.J.A., 2013. Advances in the neuroimaging of panic disorder. Hum. Psychopharmacol. 28, 608e611. nyi, A., Frecska, E., Bagdy, G., Re vai, K., 1988. Panic attacks as a consequence of Pere chronic corticosteroid therapy? Eur. J. Psychiatry 2, 69e74 n.d. Poblete, A.C., Herskovic, M.V., Eva, C.P., 2006. Panic attacks in a patient treated with isotretinoin for acne. Report of one case. Rev. Med. Chil. 134, 1565e1567. Quinn, J.C., 2015. Complex membrane channel blockade: a unifying hypothesis for the prodromal and acute neuropsychiatric sequelae resulting from exposure to the antimalarial drug mefloquine. J. Parasitol. Res. http://dx.doi.org/10.1155/ 2015/368064. Restak, R.M., 1972. Pseudotumor cerebri, psychosis, and hypervitaminosis A. J. Nerv. Ment. Dis. 155, 72e75. Ritchie, E.C., Block, J., Nevin, R.L., 2013. Psychiatric side effects of mefloquine: applications to forensic psychiatry. J. Am. Acad. Psychiatry Law 41, 224e235. Roy-Byrne, P.P., Craske, M.G., Stein, M.B., 2006. Panic disorder. Lancet 368, 1023e1032. Schneider, C., Adamcova, M., Jick, S.S., Schlagenhauf, P., Miller, M.K., Rhein, H.-G., Meier, C.R., 2013. Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders. Travel. Med. Infect. Dis. 11, 71e80. Sheehan, D.V., Burnham, D.B., Iyengar, M.K., Perera, P., Paxil CR panic disorder study group, 2005. Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. J. Clin. Psychiatry 66, 34e40. Simon, N.M., Otto, M.W., Smits, J.A.J., Nicolaou, D.C., Reese, H.E., Pollack, M.H., 2004. Changes in anxiety sensitivity with pharmacotherapy for panic disorder. J. Psychiatr. Res. 38, 491e495. Stahl, S.M., 1998. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J. Affect. Disord. 51, 215e235. Strahan, J.E., Raimer, S., 2006. Isotretinoin and the controversy of psychiatric adverse effects. Int. J. Dermatol 45, 789e799. Sweetman, S., 2011. Martindale the Complete Drug Reference. Pharmaceutical Press, London. , G., Fourrier-Re glat, A., Haramburu, F., Thiessard, F., Roux, E., Miremont-Salame gaud, B., 2005. Trends in spontaneous adverse drug reaction Tubert-Bitter, P., Be reports to the French pharmacovigilance system (1986-2001). Drug. Saf. 28, 731e740. Vial, T., 2016. French pharmacovigilance: missions, organization and perspectives. Therapie 71, 143e150. Weber, J., 1984. Epidemiology of adverse reactions to nonsteroidal antiinflammatory drugs. New York. In: Rainsford, K.D., Velo, G.P. (Eds.), Advances in Inflammation Research, pp. 1e6. Yates, W.R., 2009. Phenomenology and epidemiology of panic disorder. Ann. Clin. Psychiatry 21, 95e102.
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Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database Delphine Abadie a, *, Anaïs Essilini a, Virginie Fulda b, Aurore Gouraud c, €lle Micallef e, François Montastruc a, Jean Louis Montastruc a lissa Ye le he -Okouma d, Joe Me Department of Medical and Clinical Pharmacology, Toulouse University Hospital, Faculty of Medicine, 37 all ees Jules Guesde, 31000 Toulouse, France ^pital Europ Regional Pharmacovigilance Center, Ho een Georges Pompidou, 20-40 rue Leblanc, 75015 Paris, France c Regional Pharmacovigilance Center, Hospices Civils de Lyon, 162 avenue Lacassagne, 69424 Lyon, France d ^pitaux de Nancy, 29 Avenue du Mar Regional Pharmacovigilance Center, Ho echal de Lattre de Tassigny, 54035 Nancy, France e ^pital Sainte-Marguerite AP-HM, 270 boulevard de SaintRegional Pharmacovigilance Center, Department of Medical and Clinical Pharmacology, Ho Marguerite, 13009 Marseille, France a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 June 2016 Received in revised form 3 February 2017 Accepted 8 February 2017
Background: The potential role of drugs in the onset of panic attacks (PAs) is poorly understood. Aim: The objective of our study was to characterize drug-induced PAs. Method: We performed an analysis of PAs registered in the French pharmacovigilance database between 01/01/1985 and 05/11/2014. Results: Among the 163 recorded cases, 136 (83.4%) were directly related to drugs, mainly antidepressants (11.3%, mainly serotonin reuptake inhibitors), mefloquine (7.2%), isotretinoin (5.2%), rimonabant (3.6%) and corticosteroids (4.7%). PAs are labelled in the Summary of Product Characteristics (SmPC) for a minority (8.6%) of these drugs. In 31.4% of these cases, withdrawal of the suspected drug was performed more than a week after the onset of PAs. PAs could also be secondary to another adverse drug reaction (ADR; n ¼ 14, 8.6%), mainly an allergy to antineoplastic or immunomodulating agents. In 13 cases (8.0%), PAs occurred during a drug-withdrawal syndrome, mainly after benzodiazepines or opioids. Most cases (73%) involved patients without any previous psychiatric disorder. Conclusion: This is the first pharmacoepidemiological study about iatrogenic PAs. Beside antidepressants, the most often encountered drugs are not indicated for psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians, especially since PAs are generally not labelled in SmPCs of the suspected drugs. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Panic attack Adverse drug reaction Pharmacovigilance database
1. Introduction A panic attack (PA) is an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, with occurrence of 4 or more of cardiovascular (palpitations …), autonomic (sweating …), pulmonary (sensation of smothering …), neurological (trembling …), gastrointestinal (nausea …) or psychological (derealization …) symptoms (American Psychiatric Association, 2016).
* Corresponding author. Present address: Department of Medical and Clinical -Salpe ^trie re Hospital, 47-83 Pharmacology, Regional Pharmacovigilance Center, Pitie ^pital, 75013 Paris, France. Boulevard de l'Ho E-mail address: [email protected] (D. Abadie). http://dx.doi.org/10.1016/j.jpsychires.2017.02.008 0022-3956/© 2017 Elsevier Ltd. All rights reserved.
PAs occur across all cultures and nations and are common in the general population (Kessler et al., 2006; Yates, 2009). According to an American nationwide study, lifetime rates of PA prevalence are elevated, with almost a third of patients reporting at least one PA during their life (Kessler et al., 2006). Recurrent unexpected PAs can lead to panic disorder (PD), which is characterized by longer than 1 month of: (1) subsequent persistent worry about having another attack or consequences of the attack, or (2) significant maladaptive behavioral changes related to the attack (American Psychiatric Association, 2016). Several factors could contribute to the origin of PAs, including genetic (genes conferring vulnerability), psychopathological (cognitive distorsions and misinterpretations of somatic
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experiences) and neurobiological ones (Dresler et al., 2013; Gorman et al., 2000; Millan, 2003; Roy-Byrne et al., 2006). In the widely acknowledged revised version of their 1989 neuroanatomical hypothesis for PD, Gorman suggested that panic originates in an abnormally sensitive “fear network” in the brain, that is centered in the amygdala which stands as the central point for dissemination of information and that coordinates fear responses (Gorman et al., 2000, Fig. 1). According to this model, the sensory input for the conditioned stimulus runs through the anterior thalamus to the amygdala, which in turn stimulates: (i) the parabrachial nucleus, producing an increase in respiratory rate; (ii) the lateral nucleus of the hypothalamus, activating the sympathetic nervous system and causing sympathetic discharge; (iii) the locus ceruleus, resulting in an increase in noradrenaline (NA) release and contributing to increases in blood pressure, heart rate, and the behavioral fear response; and (iv) the paraventricular nucleus of the hypothalamus, rising the release of adrenocorticoids (Gorman et al., 2000, Fig. 1). Consistent with Gorman's hypothesis, neuroimaging studies have subsequently reported in patients with PD an increased reactivity of the amygdala with volume reduction and structural deficit (Kim et al., 2012). Modern neuroimaging techniques since 2000 have also pointed to (i) the involvement of other cortical areas and other brain circuitry (e.g. the insula and anterior cingulate cortex) (Dresler et al., 2013; Pannekoek et al., 2013) and (ii) other neurochemical alterations within the fear network such as altered GABAergic [particularly in frontal and cingulate cortex (Long et al., 2013)] and serotonergic transmission [particularly in the raphe nuclei (Nash et al., 2008; Neumeister et al., 2004)]. Currently, the potential role of drugs in the onset of PAs is poorly understood. No pharmacoepidemiological study has been performed to evaluate, at a population level, the characteristics of drug-induced PAs. Consequently, more information would be required for a better understanding of iatrogenic PAs in routine clinical practice. Our objective was to analyze characteristics of PAs registered in the French PharmacoVigilance Database (FPVD), especially involved drugs.
61
2. Material and methods 2.1. Data source The French Pharmacovigilance system was first established in 1973 and consists of a network of 31 regional centers (Moore et al., 1995; Vial, 2016). The FPVD was subsequently established in 1985 to record any Adverse Drug Reaction (ADR) spontaneously notified by health professionals. Reporting ADRs to the French regional centers has been mandatory for any drug prescriber (physician, dentist, or midwife) or pharmacist in France since 1995 (Moore et al., 1995; Vial, 2016). Other healthcare professionals and more recently patients (decree of June 10th, 2011) can also report ADRs. In 2016, more than 623,000 reports of ADRs are registered in this database. For each report, information about patient (age, gender, past medical history), ADR [type (coded according to the Medical Dictionary for Drug Regulatory Activities MedDRA (Brown et al., 1999), date of onset, duration and evolution], and drug exposure [name, intake dates, doses] are recorded. A detailed summary of clinical description is added at the end of each pharmacovigilance case report. For all reports, a causality assessment (“imputability” or “imputation”) is done for each drug using the French Pharmacovigilance System's method (Miremont-Salame et al., 2016). If causality is found between the drug and the occurrence of the ADR, drugs are defined as “suspected” and if not, they are defined as “associated” (non-suspected) (Miremont-Salame et al., 2016). 2.2. Data analysis We performed an analysis of spontaneous reports of PAs registered in the FPVD between 01/01/1985 and 05/11/2014 under the MedDRA terms “Panic attacks and disorders” (High Level Term) or “Anxiety attack” (Low Level Term). Clinical symptomatology of each reported case was thoroughly examined by 2 pharmacovigilance specialists (DA, JLM) and 1 psychopharmacologist (FM). Cases corresponding to another medical diagnosis or those without sufficient data were excluded. For each case, we systematically recorded variables related to the patient (age, gender and medical history),
Fig. 1. Neuroanatomical pathways potentially involved in panic attacks according to Gorman's hypothesis (Gorman et al, 2000).
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PA (date of onset, “seriousness”, clinical characteristics, management and outcome) and suspected drugs (name, intake dates, doses). A “serious” ADR is defined as any untoward medical occurrence that at any dose results in death, requires hospital admission or prolongation of existing hospital stay, results in persistent or significant disability/incapacity or is life threatening (Edwards and Aronson, 2000).
agents. The second most often encountered ADRs inducing PAs were psychiatric ones (n ¼ 5, 36%): hallucinations (zolpidem, oxycodone) or insomnia (mefloquine, morphine). In the 2 last cases, PAs occurred in the context of nausea and neurological disorders (dizziness or coordination disorder) induced by risperidone or ropinirole. Anxiety is labelled in the SmPC only for mefloquine and risperidone, and PA only for mefloquine (European Medicines Agency, 2016).
3. Results 3.1. General characteristics of cases Of the 555,813 notifications recorded in the FPVD, 189 (0.03%) were reported as a PA, among which 163 (86.2%) were analyzed. Average age of patients was 42.1 ± 18.7 years, mostly adults (80.3% between 15 and 65 years, including 46.0% between 18 and 45 years). Children (under 15 years of age: 5.5%) and elderly patients (more than 65 years of age: 12.9%) were in minority. Reports concerned mainly females (n ¼ 104; 63.8%). A medical history of psychiatric disorder was reported for 27.0% of patients (mostly a depressive disorder: 15.3%). Very few patients (4.3%) had a past medical history of anxiety (including those with previous PAs). A minority of cases were “serious” (n ¼ 27, 16.6%), including 25 hospital admissions or prolongations of existing hospital stay and 2 significant disabilities/incapacities.
3.3.3. PAs occurring in the context of a withdrawal syndrome (n ¼ 13, 8.0%) Mean age of patients was 41.4 years (±10.7), majority females (n ¼ 10, 76.9%). The most often involved drugs were benzodiazepines (n ¼ 5, mainly prazepam) and opioid analgesics (n ¼ 5, mainly tramadol). 3.4. Management and evolution of cases (Table 2) In the group of PAs directly induced by drugs, the suspected drug was generally discontinued after PAs onset. Although the drug was frequently stopped rapidly (the day of the PA onset), in almost a third of cases, it took more than a week before a practitioner finally discontinued it. On the whole, around 1 out of 3 patients needed a pharmacological treatment for PAs, mainly an anxiolytic alone. Even if most of patients suffered from repeated PAs, the outcome was generally favorable.
3.2. General repartition of suspected drugs (Table 1) 3.5. Focus on « serious » cases A total of 194 drugs was suspected (mean of 1.2 suspected drugs per report). The most often encountered drugs were antidepressants [mainly serotonin reuptake inhibitors (SRIs)], followed by mefloquine, isotretinoin, rimonabant and corticosteroids. 3.3. Etiological groups of PAs A detailed analysis of case reports allowed us to distinguish 3 etiological groups of PAs: 1) PAs directly related to drugs [i.e. PAs occurring during treatment with the suspected drug], 2) PAs secondary to another ADR [i.e. PAs occurring during treatment with the suspected drug and due to another ADR induced by this drug] and 3) PAs occurring in a context of a drug-withdrawal syndrome. 3.3.1. PAs directly induced by drugs (n ¼ 136, 83.4%) Mean age of patients was 42.5 years (±19.4), mainly females (n ¼ 82, 60.3%). Most of time (n ¼ 59, 46%), PAs occurred during the hours immediately following introduction of the suspected drug. The most often involved drugs were antidepressants [n ¼ 19, mostly SRIs and especially paroxetine (n ¼ 5)] and the great majority (93%) of related PAs occurred during the first week of treatment. The most often encountered drugs following antidepressants were (n 3): mefloquine (n ¼ 13), isotretinoin (n ¼ 9) rimonabant (n ¼ 7), corticosteroids [prednisone (n ¼ 3), budesonide (n ¼ 3)], pregabaline (n ¼ 4) and methylphenidate (n ¼ 3). PAs are labelled in the Summary of Product Characteristics (SmPC) for only 8.6% of the 105 suspected drugs (e.g. SRIs, mefloquine or rimonabant) (European Medicines Agency, 2016). Most frequently (91.4%), PAs are not labelled (e.g. isotretinoin, corticosteroids or methylphenidate). Anxiety is labelled for about half (49.5%) of the suspected drugs (e.g. SRIs, mefloquine, rimonabant or isotretinoin) (European Medicines Agency, 2016). 3.3.2. PAs secondary to another ADR (n ¼ 14, 8.6%) Mean age of patients was 39.4 years (±18.6), mainly females (n ¼ 12, 86%). These PAs were mainly (n ¼ 7, 50%) the consequence of an allergic reaction to antineoplastic or immunomodulating
3.5.1. Hospital admissions or prolongations of existing hospital stay (n ¼ 25) Mean age of patients was 42.1 ± 21.3 years, mostly females (n ¼ 13). In the vast majority of the corresponding cases (n ¼ 21), the PA was directly induced by drugs [most often involved drugs: SRIs (n ¼ 2), mefloquine (n ¼ 2) or rimonabant (n ¼ 2)], in 3 cases the PA occurred in the context of a withdrawal syndrome (bromazepam, methadone or morphine), and in the last case, the PA was due to another ADR (allergic reaction due to paclitaxel). Most of the patients (n ¼ 22) fully recovered, one recovered with sekelae (persistent anxiety after isotretinoin treatment) and 2 did not recovered (persistent PAs after mefloquine or varenicline treatment). 3.5.2. Disabilities/incapacities (n ¼ 2) Two young women (18 and 19 years-old) presented significant and severe disability/incapacity due to persistent PAs (isotretinoin or adalimumab). 4. Discussion As far as we know, this is the first published study that investigates at a population level and through a large pharmacovigilance database the characteristics of iatrogenic PAs. Our results show that, in real clinical practice, various drugs can induce a PA, the first ones being antidepressants and especially SRIs, followed by the widely used antimalarial drug mefloquine, the anti-acne drug isotretinoin, rimonabant, a weight loss drug, and corticosteroids. Our study suffers from some compulsory methodological drawbacks, as with all other studies using a pharmacovigilance database [underreporting, biases in reporting, indication bias, lack of the total number of treated patients (Thiessard et al., 2005; Weber, 1984)]. Nonetheless, it should be noted that our aim was not to describe exhaustively all cases of iatrogenic PAs occurring in France, but rather to review the drugs involved in reports of PAs. Moreover, despite these limitations, compared with previous
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Table 1 Drugs involved in Panic Attacks (PAs) registered in the French Pharmacovigilance database according to Anatomical Therapeutic Classificationa. Drug
n
(%)
A Alimentary tract and metabolism A08 Antiobesity preparations A08AX Other antiobesity drugs
15 8 7
(7.7) (4.1) (3.6)
rimonabant
7
(3.6)
D Dermatologicals D10 Anti-acne preparations D10BA Retinoids for treatment of acne
12 10 10
(6.2) (5.2) (5.2)
isotretinoin
10
(5.2)
H Systemic hormonal preparations H02 Corticosteroids for systemic use H02AB Glucocorticoids
7 6 6
(3.6) (3.1) (3.1)
prednisone
3
(1.6)
N Nervous system N03 Antiepileptics N03AX Other antiepileptics
79 8 7
(40.7) (4.1) (3.6)
pregabalin
5
(2.6)
N06 Psychoanaleptics N06A Antidepressants N06AB Selective serotonin reuptake inhibitors
28 22 12
(14.4) (11.3) (6.2)
paroxetine
6
(3.1)
N06AX Other antidepressants
10
(5.2)
mianserin
4
(2.1)
N06B Psychostimulants N06BA Centrally acting sympathomimetics
4 4
(2.1) (2.1)
methylphenidate
3
(1.6)
P Antiparasitic products P01 Antiprotozoals P01B Antimalarials P01BC Methanolquinolines
15 15 15 14
(7.7) (7.7) (7.7) (7.2)
mefloquine
14
(7.2)
R Respiratory system R03 Drugs for obstructive airway diseases R03BA Glucocorticoids
14 6 3
(7.2) (3.1) (1.6)
budesonide
3
(1.6)
Total
194
(100.0)
a b c
Time to PA onsetb
Anxiety labelledc
PA labelledc
32
Yes
Yes
51
Yes
No
1
No
No
2
Yes
Yes
0,5
Yes
Yes
2
No
Yes
3
Yes
No
2
Yes
Yes
11
Yes
No
Data not shown if less than 3 patients were exposed to the drug. Median, in days. Summary of Products Characteristics.
publications about iatrogenic PAs (isolated case reports), our systematic analysis of French notifications is original from a methodological point of view. It offers a picture more in line with usual medical practice and therefore constitutes a unique approach to improve our knowledge on circumstances of occurrence of this relatively unknown (and rare) ADR. In terms of age and gender, our patients were comparable to those described in the literature as having a high risk of suffering from PAs. Effectively, female gender appears to constitute a significant risk factor for PAs (Kessler et al., 2006). Moreover, PAs appear to be more likely in those in the 18-to-45 year age group and lower rates are typically seen in persons age 65 and older, which may reflect a tendency for PA to abate over time (Kessler et al., 2006; Yates, 2009). It is only for a minority of patients that the first lifetime PA appears before fifteen years old (Kessler et al., 2006). We surprisingly found a low rate of patients with a past medical history of psychiatric disorder (27%), especially for anxiety and PA (4%). In contrast, epidemiological studies have reported, in patients with at least 1 lifetime PA, a higher percentage (72%) of comorbidity
with another psychiatric disorder (Kessler et al., 2006). Thus, our population is clearly different regarding psychiatric history from that who usually experiences typical PAs. To our opinion, the iatrogenic hypothesis seems highly probable to explain why these patients without preexisting history of anxiety begin one day to develop their first PA, given (i) the temporal coexistence with the culprit drug exposure and (ii) the underlying pharmacological plausibility (see below). We could also assume that without exposure to the culprit drug, most of our patients might perhaps have never experienced any PA. Few studies have suggested that ADRs could have a psychological impact on patients' lives (Butt et al., 2011). To our knowledge, our study is the first to show that, in routine clinical practice, stress induced by an ADR can trigger true PA. As this point was not previously reported in the literature, it constitutes one of the major findings of the present work. Results of epidemiological studies tend to illustrate that anxiety disorders in general are insidious and characterized by a chronic clinical course with low rates of recovery and relatively high probability of recurrence (Hendriks et al., 2013). The high rate of
64
D. Abadie et al. / Journal of Psychiatric Research 90 (2017) 60e66 Table 2 Management and evolution of panic attacks registered in the French pharmacovigilance database between 1985 and 2014. n (%) Discontinuation of the suspected drug (n ¼ 152)a No Yes Rechallenge Positive rechallenge
7 (4.6) 145 (95.4) 25 (17.2) 17 (68.0)
Time to discontinuation of the suspected drug (n ¼ 118, in days)a <1 44 (37.3) [1e7] 37 (31.4) >7 37 (31.4) Hospitalization (n ¼ 163) No Yes
138 (84.7) 25 (15.3)
Pharmacological treatment (n ¼ 145) No Yesb 1/Anxiolytic only Benzodiazepine H1 antagonist 2/Benzodiazepine þ antidepressant 3/Antidepressant only
97 (66.9) 48 (33.1) 24 (50.0) 15 (31.3) 6 (12.5) 7 (14.6) 5 (10.4)
Psychiatric follow up (n ¼ 140) No Yes
121 (86.4) 19 (13.6)
Number of panic attacks (n ¼ 137) 1 Multiple
41 (29.9) 96 (70.1)
Evolution (n ¼ 152) Recovered Not recovered Recovered with sekelaec
125 (82.2) 25 (16.4) 2 (1.3)
a
Panic attacks directly induced by drugs. Data not shown if less than 5 patients were exposed to the pharmacological treatment. c Residual anxiety. b
recovery observed in our study (82.2%) could be due to the disappearance of the PA-triggering factor, since in most cases the culprit drug was stopped. On the contrary, predisposing/triggering factors for typical PAs (e.g. genetic predisposition, stressfull living conditions) are not often easily identifiable or removable. Another point to consider is due to the fact that our population was medically followed-up, since the great majority of culprit drugs need a medical prescription in France. Conversely, for many patients with anxiety disorders, it may last months, even years until they are referred to a specialist. In terms of PA management, we observed that, in about a third of cases, cessation of the suspected drug was performed more than a week after the PA onset. This high proportion of cases with delayed management reveals that there is still work to be done to sensitize physicians to the fact that PAs can be drug-induced. This is all the more important since PAs are generally not labelled in SmPCs of the suspected drugs. From a practical point of view, our results indicate that a systematic anamnesis about drugs should be involved in each etiological research of PA. The present work also allows discussion of several interesting points from a pharmacological point of view. Firstly, we found that a large variety of drugs with distinct mechanisms of action are capable of producing PA in susceptible patients. According to the Gorman's fear network model and subsequent discoveries on
neurochemical alterations within this fear network, the heterogeneity of culprit drugs could be explained by (i) the several neurotransmitters involved in the underlying mechanisms of PA, with a high degree of interconnectivity (Dresler et al., 2013; Gorman et al., 2000; Millan, 2003; Roy-Byrne et al., 2006) and (ii) the fact that a drug that causes PA does not only interact with a specific cerebral area but, rather, activates the entire fear network (Gorman et al., 2000). Antidepressants and especially SRIs have been used for the treatment of several anxiety disorders, including PD (Lai and Wu, 2013; Sheehan et al., 2005; Simon et al., 2004). However, antidepressants only exert their effect after 3e4 weeks of repeated administration, and during the initial phase of treatment, they can paradoxically produce an initial exacerbation of anxiety symptoms, especially in PD (Akimova et al., 2009; Nascimento et al., 2014). Consistently with these data, in our study, the great majority of antidepressant-induced PAs occurred during the first week of treatment. This phenomenon could be due to an oversensitivity of key serotonin postsynaptic receptors (Coplan et al., 1992), which could be reversed to its opposite in synapses regulating anxiety as the result of adaptive mechanisms, such as down regulation of post synaptic receptors (Stahl, 1998). It has been shown in preclinical models that elevation in anxiety acutely after SRIs can be blocked by antagonists of 5HT-2 receptors (Bagdy et al., 2001). The opposite effects of SRIs between acute and subchronic administrations are also illustrated by neuroimaging findings showing that acute SRI administration to man enhances amygdala reactivity (Bigos et al., 2008) whilst subchronic treatment reduces it (Harmer et al., 2006). The accumulated preclinical and clinical (several case reports, observational studies and randomized controlled trials) evidence supports mefloquine, a widely used antimalarial drug, being psychoactive and neurotoxic (Schneider et al., 2013). Mefloquine has been associated with a variety of neuropsychiatric reactions such as PAs (European Medicines Agency, 2016; Meier et al., 2004). The underlying mechanism is not clear, but mefloquine is highly lipophilic and may accumulate in the limbic system (which includes the amygdala) relative to other areas in the brain, where it acts to disrupt a form of cellular electrical communication that is essential for coordinated inhibitory control (Ritchie et al., 2013). In particular, available evidence suggests that mefloquine critically affects synchrony of GABAergic neurons through a blockade of membrane channels (connexins and KATP channels)(Quinn, 2015). Isotretinoin is a retinoid derivative from the essential nutrient vitamin A, often used in adolescents with severe acne. Even if its psychiatric risk has been a controversial topic for many years (Strahan and Raimer, 2006), the available literature data strongly suggest a link with depression (Ludot et al., 2015). The risk of anxiety has been less investigated, but isolated case reports of isotretinoin-related PAs have been published (Poblete et al., 2006). Psychiatric ADRs have been described in patients exposed to high doses of vitamin A (Restak, 1972). It has been shown that, in the hypothalamus, endogenous retinoic acid regulates some genes involved in corticotrophin-releasing factor (CRF) synthesis, a key regulating factor in the HPA axis, a central component in the response to stress (Abelson et al., 1996; Bremner et al., 2012; Mathew et al., 2008) which is dysregulated in patients with PD (Abelson et al., 2007). Exposure of cells to isotretinoin, which is isomerized in tissue to the active all-trans retinoic acid, results in inappropriate gene transcription which may contribute to HPA axis hyperactivity (Bremner et al., 2012). Moreover, a neuroimaging study showed that isotretinoin treatment was associated with decreased brain metabolism in the prefrontal cortex (Bremner et al., 2005), and a neurocognitive deficit in this area could be involved in an inappropriate activation of the “fear network” via misguided excitatory input to the amygdala (Gorman et al., 2000).
D. Abadie et al. / Journal of Psychiatric Research 90 (2017) 60e66
Rimonabant is a selective cannabinoid type-1 (CB1) receptor antagonist used as an adjunct for the treatment of obesity, until its withdrawal in Europe in 2009 after concern about psychiatric ADRs (serious depressive states and suicides) (Sweetman, 2011). Anxiety occurs commonly with this drug and can lead to PAs (European Medicines Agency, 2016). Endocannabinoid system is known to play a key role in mental processes, and, as a function of personality and the precise circumstances of testing, cannabinoids have been found to either relieve or induce anxiety in man (Millan, 2003). Notwithstanding these complex effects, CB1 receptor antagonists generally provoke an increase in anxiety in rodents (Millan, 2003). This could be explained by the fact that cannabinoids modulate the release of several neurotransmitters implicated in anxious states (such as glutamate or NA) (Millan, 2003). The psychostimulant effects of glucocorticoïds (GCs), the most commonly prescribed anti-inflammatory/immunosuppressant drugs worldwide, are well known. GCs can induce a large spectrum of psychopathological disturbances, ranging from agitation to severe mental disorders such as psychosis (Judd et al., 2014). Few case reports have also implicated GCs in causing PAs (Iskandar et al., nyi et al., 1988). A recent cohort study found a significant 2011; Pere increase of PD incidence during the first 3 months of a course of oral GC treatment (Fardet et al., 2012). High levels of cortisol, the main endogenous glucocorticoid, inhibit brain-derived neurotrophic factor, which is important for maintaining neural architecture in key brain regions such as the hippocampus and prefrontal cortex (Duman and Monteggia, 2006). Neuroimaging studies have shown functional changes in several brain regions after acute or chronic GCs treatment (Judd et al., 2014), including atrophy of the right amygdala (Brown et al., 2008), which is thought to predispose to PD (Kim et al., 2012). Methylphenidate, a piperidine derivative structurally related to amphetamine, is used in attention-deficit hyperactivity disorders and narcolepsy. Amphetamines appear to exert most of their effects in the central nervous system by releasing biogenic amines (mostly noradrenaline and dopamine) from their storage sites in nerve terminals and by blocking their reuptake (Brunton et al., 2011). Some studies revealed that chronic use of methylphenidate was associated with neurochemical alterations of the amygdala, including oxidative stress and inflammation (Motaghinejad et al., 2016). A recent neuroimaging study showed multiple effects of methylphenidate on brain functions, including an increase of thalamic connectivity to the hippocampus and amygdala, which may speak to its alerting-enhancing effects (Farr et al., 2014). In contrast, for one drug, PAs cannot be explained by a simple pharmacological mechanism. Pregabalin is a GABA analog used worldwide as an antiepileptic but also in the treatment of generalised anxiety disorder (Frampton, 2014). Its precise mechanism of action is still discussed [decrease in calcium-dependent release of neurotransmitters implicated in anxiety disorders, including NA (Dooley et al., 2000)]. It is somewhat surprising to observe PAs with this drug. Our cases are all the more interesting in that (i) pregabalin was always prescribed for pain (and not for anxiety), (ii) none of the patients had a past medical history of anxiety or PAs and (iii) chronology was suggestive since, in each case, evolution was favorable after pregabalin discontinuation. Even if PAs are labelled in pregabalin SMPc (European Medicines Agency, 2016), literature data rather suggest that pregabalin-induced PAs or anxiety only occur in the context of a withdrawal syndrome. In conclusion, this is the first study about drug-induced PAs based on a large pharmacovigilance database. Our results highlight that various drugs induce PAs in routine clinical practice, the first ones being antidepressants, especially SRIs. Interestingly, the most often encountered drugs following antidepressants (mefloquine, isotretinoin, rimonabant and corticosteroids) are not indicated for
65
psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians. This is all the more important since PAs are generally not labelled in SmPCs of the suspected drugs. Role of funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Contributors DA, AE, FM and JLM participated in the study design, planning, and analyses of cases. DA and AE managed the literature searches and interpretation of the data. FM and JLM took part in the interpretation of the data. DA wrote the first draft of the manuscript. FM and JLM critically revised the manuscript for important intellectual content. All authors contributed to and have approved the final manuscript. Conflict of interest None to declare. Abbreviations ADR CB1 CRF FPVD GC HPA 5HT MedDRA NA PA PD SmPC SRI
adverse drug reaction cannabinoid type-1 corticotrophin-releasing factor French pharmacovigilance database glucocorticoïd hypothalamus/pituitary/adrenal 5-hydroxytryptamine medical dictionary for regulatory activities noradrenaline panic attack panic disorder Summary of Product Characteristics serotonin reuptake inhibitor
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