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Donepezil-associated manic episode with psychotic features: a case report and review of the literature
General Hospital Psychiatry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Donepezil-associated manic episode with psychotic features: a case report and review of the literature☆ Ana Hategan, M.D. a,⁎, James A. Bourgeois, O.D., M.D. b a Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada b Department of Psychiatry/Langley Porter Psychiatric Institute, Consultation/Liaison Service, University of California San Francisco Medical Center, San Francisco, CA, USA
a r t i c l e
i n f o
Article history: Received 3 May 2015 Revised 14 September 2015 Accepted 16 September 2015 Available online xxxx Keywords: Donepezil Cholinesterase inhibitors Mania Neurocognitive disorders Dementia
a b s t r a c t Objective: Reports of manic episodes associated with the use of cholinesterase inhibitors (including donepezil) are limited. Despite the previous notion of procholinergic drugs potentially inducing depression, the contemporary evidence for cholinesterase inhibitors appears to also indicate a trend for elevated mood (in patients with or without a history of depressive disorder). Method: Case report. Results: The authors report a case of a manic episode with psychotic features associated with the up-titration of donepezil in a patient with Alzheimer’s disease and a distant history of major depression but without a preexisting bipolar disorder. Conclusion: Pathophysiology of donepezil-induced mania appears to contradict the traditional cholinergicadrenergic hypothesis. Donepezil-associated mania should be suspected after donepezil initiation/dose up-titration when correlated to new onset of mania. Donepezil should be used more cautiously in patients with current or previous mood episodes or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Although this requires further investigation in different patient populations, there may be subtypes of older patients with neurocognitive disorders who are particularly vulnerable to activation effects of cholinesterase inhibitors. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Old anecdotal reports have indicated that exposure to cholinomimetic drugs, such as pilocarpine, physostigmine and organophosphate insecticides, may in fact have a depressogenic or antimanic effect [1]. In 1972, Janowsky et al. [2] postulated the classical cholinergic-adrenergic hypothesis, possibly involving reciprocating and balancing effects of procholinergic agents on mood, in that excess acetylcholine was associated with depression and decreased acetylcholine was associated with mania. According to this hypothesis, cholinesterase inhibitors (ChEIs) such as donepezil approved to treat memory dysfunction in Alzheimer’s disease (AD) [3], should not cause mania unless there are other relevant contributory factors not captured by this explanatory model. This hypothesis led to the study of off-label use of donepezil as an augmentation agent for commonly used mood stabilizers (e.g., lithium
☆ Conflict of Interest and Source of Funding: The authors report no relevant financial relationships and no conflict of interest. ⁎ Corresponding author. Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, St. Joseph’s Healthcare Hamilton, West 5th Campus, 100 West 5th Street, Hamilton ON, Canada L8N 3K7. E-mail address: [email protected] (A. Hategan).
or valproate) for treatment of refractory mania, which has shown mixed results [4–6]. In particular, two double-blind, placebocontrolled studies have failed to show any benefit [5,6]; continuation of therapeutic doses of the primary mood stabilizer was shown to be superior to augmentation with donepezil in one study [5], whereas donepezil had some benefit on the first day but did not provide any significant benefits in the long term in the other study [6]. Moreover, trials of donepezil assessing cognitive dysfunction in patients with bipolar disorder particularly warned of a concerning trend for donepezil to destabilize bipolar I patients [7,8]. Therefore, the previously established notion of increased cholinergic tone being associated with depression (or an antimanic effect) may not be as sound as once hypothesized. Donepezil-related adverse events of mania or hypomania per se were not identified in clinical trials leading to regulatory approval; however, irritability, emotional lability, restlessness, aggression, paranoia and delusions were reported [3]. There are abundant reports in the medical literature of various drug classes reported to induce mania (e.g., antidepressants, corticosteroids, levodopa, thyroxine, chloroquine) [9]. ChEIs have also been studied for their effects on mood and behavior in the treatment of AD-related neuropsychiatric symptoms (NPS) (e.g., apathy, depression, psychosis, sleep disturbance and agitation), which can further impact patients’ performance on instrumental and basic activities of daily living [10]. In this population, donepezil
http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004 0163-8343/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
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A. Hategan, J.A. Bourgeois / General Hospital Psychiatry xxx (2015) xxx–xxx
has been associated with a mild improvement from baseline for the responders on NPS in AD, including delusions, agitation, anxiety, disinhibition and irritability; these effects were dose dependent [11,12]. Our observations based on the following case description might add to the challenge of the cholinergic-aminergic hypothesis of mood disorders and suggest a need for revising the role of ChEIs in this hypothesis. 2. Case report A 72-year-old Caucasian female with a recent diagnosis of a probable major neurocognitive disorder due to AD was admitted to a psychiatric unit with a 1-month history of increasing cognitive and behavioral disorganization, pressured speech, hyperreligiosity, hypersexuality, delusions, insomnia, agitation and violent behavior. This symptomatology occurred within 1 week of increasing her donepezil from 5 mg to 10 mg daily. Donepezil was suspected to have induced her new NPS and was discontinued 3 days prior to admission. She continued to endorse delusional conviction that her husband had had an affair with a 24-year-old woman with whom he had a 1-year-old son, which aggravated marital discord. The patient disclosed to her daughter that, during the previous night, she had attempted to stab her husband, having put a knife to his chest during his sleep, but then changed her mind and stopped short of physically harming him. This disclosure precipitated admission to the hospital. Her past psychiatric history included a single major depressive episode 8 years previously, which fully remitted on duloxetine 30 mg daily. Her medical history included fibromyalgia, for which duloxetine 30 mg daily had been also used and continued at unchanged dosage. She had hypertension, which was treated with ramipril 2.5 mg daily. Her family psychiatric history included several biological relatives with major depressive disorder. On examination, the patient displayed a marked psychomotor agitation, pressured speech, labile affect (with marked fluctuations of euphoria, irritability and tearfulness), delusions of jealousy and grandiosity, flight of ideas and loosening of associations. She denied any suicidal or homicidal ideation, and there were no hallucinations. Her insight and judgment were impaired. She was alert, oriented to place and disoriented to time. Montreal Cognitive Assessment (MoCA) score was 15 out of 30 on admission. The physical examination and laboratory investigations (including hematologic, electrolyte, renal, hepatic, thyroid and urinalysis parameters) were all normal. Computed tomography of brain revealed patchy, confluent areas of white matter hypoattenuation within the subcortical, periventricular and deep white matter tracts, which were reported as age-related chronic microangiopathic changes. Her daughter was the proxy decision maker for medical treatment. Medication changes upon admission included discontinuation of duloxetine and initiation and up-titration of risperidone to 1.5 mg daily. Donepezil was not restarted. Her fibromyalgia symptoms did not worsen. Her psychiatric symptoms fully remitted within 2 weeks, at which time her mental status examination revealed euthymic affect, goal-directed and coherent thought process, no delusional thinking and no suicidal or homicidal ideation. A repeated MoCA remained stable at 15 out of 30. She was discharged to an outpatient clinic for follow-up and tapering of risperidone dose. At an outpatient visit 10 weeks later, her risperidone had been tapered and completely discontinued and she remained off of psychotropic medication thereafter. Particularly, she was not rechallenged with a cholinesterase inhibitor or duloxetine and was not started on memantine at her and her daughter’s choice. Her mood had remained stable with no recurrence of manic spectrum or psychotic symptoms. 3. Discussion Table 1 describes 11 previously published cases of mania/hypomania associated with ChEIs in the treatment of neurocognitive disorders
(formerly dementia) [13–21]; eight cases alone were associated with donepezil [13–17,19,21]. The existing literature on patients with neurocognitive disorders and ChEI-associated mania does not appear to support vulnerability in any particular subtype of neurocognitive disordered patient to a manic episode; the patients had diagnoses ranging from mild to major neurocognitive disorders of various etiologies (i.e., AD, vascular or repair of a cerebral aneurysm [16]); four patients had personal history of bipolar I disorder and two also had a history of unipolar depression. As illustrated in Table 1, type and daily dose of reported ChEIs varied from donepezil 5 mg (n= 5), donepezil 10 mg (n= 3), galantamine 16 mg (n= 1), rivastigmine 3 mg (n= 1) and rivastigmine 4.6 mg (n=1). Therefore, this adverse event appears to indicate a class effect. The time to manic/hypomanic episode varied from 3 days to 3 weeks from initiation/optimization (dose up-titration) of ChEI. Resolution after ChEI discontinuation, either spontaneously or following treatment with a mood stabilizer and/or antipsychotic, varied from between 1 day to 2 weeks. Donepezil rechallenge resulted in a recurrence of mania in two patients [13–15], whereas rechallenge with a small dose of donepezil was successful in a patient who initially developed mania on rivastigmine [20]. Of concern is some evidence that donepezil could elevate mood even in healthy persons [22,23], which raises potential concerns for misuse. The rapid emergence of psychotic mania in the context of donepezil dose titration in our patient was compelling because of no preexisting history of bipolar disorder including no history of mania induced by duloxetine. This case is similar to previously reported cases of neurocognitive disorders in that the patient presented with a manic episode that commenced within days of up-titrating the donepezil dose. As this case illustrates a plausible contribution of donepezil to the patient’s emergence of mood elevation, a few differential diagnoses are further entertained. Delirium with manic and psychotic features, possibly caused by the combination of medications, might have accounted for elements of this clinical picture. This was felt to be improbable, given the lack of fluctuating level of cognitive status, no altered level of consciousness and no classic inversion of the sleep–wake cycle in this patient; i.e., there was insufficient evidence for a diagnosis of delirium at time of presentation. It is possible that her mood, psychotic and psychomotor manifestations represented distinct expressions of NPS associated with the neurocognitive disorder and not a “primary” bipolar disorder per se. However, treatment with ChEIs in AD patients has in fact demonstrated beneficial effects on NPS, as previously emphasized [10–12]. Intriguingly, the manic and psychotic symptoms in our patient resolved only after discontinuation of donepezil and duloxetine and starting risperidone, an atypical antipsychotic recommended in treatment guidelines for acute bipolar mania [24], thus supporting a plausible causal link to a bipolar diathesis. Based on the neuroimaging findings, a vascular etiology of mood elevation may have been contributory. There is increasing evidence that white matter signal changes, thought to represent areas of ischemic damage to brain tissue, may play an important role in the neurobiology of bipolar disorder, regardless of age [25]. Nevertheless, these lesions are not specific to bipolar disorder but appear at similar rates in unipolar depression and schizophrenia [25]. Therefore, the role of white matter signal changes in the pathogenesis, pathophysiology and response to treatment of manic episodes remains unclear [25]. While ruling out other vulnerability to mania was impossible in this patient, the temporal relationship between the onset of donepezil titration and psychotic mania in this patient suggests the possibility of a causal link. The question remains whether her concomitant use of the antidepressant duloxetine may have played a role. The long-term treatment with antidepressant duloxetine without previous episodes of mania in our patient appeared to favor a new onset, donepezilassociated manic episode rather than a decompensation of a preexisting bipolar diathesis. Both duloxetine and donepezil are mainly metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme, and thus, a cumulative/additive effect of duloxetine and donepezil overburdening this
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
A. Hategan, J.A. Bourgeois / General Hospital Psychiatry xxx (2015) xxx–xxx
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Table 1 Review of reported cases of cholinesterase inhibitors associated with manic/hypomanic episodes in neurocognitive disorders [13–21]. Authors/year
Reported patients
Benazzi (1998) [13], Benazzi (1999) [14], Benazzi and Rossi (1999) [15]
78 years old F
Rao et al. (2008) [16]
Collins et al. (2011) [17] Ehrt et al. (2011) [18]
Wicklund and Wright (2012) [19] Tseng and Tzeng (2012) [20] Leung (2014) [21]
Medication/ daily dose
Donepezil 5 mg 64 years old F Donepezil 5 mg 68 years old M Donepezil 5 mg 74 years old F Donepezil 10 mg 50 years old M Donepezil 5 mg 76 years old F
Donepezil 10 mg 81 years old F Rivastigmine 4.6 mg patch 76 years old M Galantamine 16 mg 65 years old F Donepezil 5 mg 79 years old M Rivastigmine 3 mg 70 years old M Donepezil 10 mg
Event
Time to event
Time to Rechallenge resolution (after discontinuation of medication)
Cognitive status
Personal and family history of psychiatric disorders
Mania
3–7 days
1–7 days
Mild to severe dementia, unspecified etiology
MDD
Mania
Hypomania
Ø
Mania
Mania
Delusional disorder
Hypomania
Ø
BD type I
Hypomania 3 weeks
Not reported
Ø
BD type I
Hypomania “A few weeks” “Quickly” after dose increase Mania 1 week 1 week
Ø
Cognitive impairment due to cerebral aneurysm repair Vascular dementia
Ø
AD dementia
Minor depressive episodes BD type I
Mania
Family history of BD and MDD
2 weeks
Ø
AD dementia
BD type I
Mania
9 days after dose increase 5 days
Not reported
Ø
Vascular dementia
None
Mania
3 days
2 days
AD dementia
None
Mania
“Days” after dose 2 weeks increase
No mania with donepezil 2.5 mg Ø
Mild cognitive impairment
Paranoid schizophrenia, alcohol dependence
Notes: Ø, no rechallenge; BD, bipolar disorder; F, female; MDD, major depressive disorder; M, male.
metabolic pathway, resulting in increased medication level of one/both of these agents, was impossible to rule out [26,27]. Given the large degree of CYP2D6 phenotypic variation, it would be important to mention that approximately 20% of the AD population may exhibit an abnormal metabolism of ChEIs (including donepezil), of which 50% of this group (i.e., 10% of the total AD population) may be hypometabolizers and therefore increasing the potential for adverse events due to ChEI toxicity [27]. It remains unclear by what mechanism donepezil can induce mania. One mechanistic hypothesis could be that an increase in acetylcholine leads to changes in neurotransmitters and neuromodulators, including dopamine, norepinephrine and serotonin [28]. In animal studies, in which manic-like behavior was explained by a hyperdopaminergic mouse model of bipolar disorder [29], acute administration of donepezil was found to be associated with (a) increase in extracellular dopamine in the cortex and dorsal hippocampus of the treated rodents, (b) increase in norepinephrine in the dorsal hippocampus and the medial temporal cortex and decreased in the ventral hippocampus and (c) decrease in serotonin levels [30]. Further investigation of the monoamine pathways plausibly implicated and comparisons among healthy young adults, cognitively intact older adults and older adults with neurocognitive disorders could identify subtypes of patients who may be particularly vulnerable to activation/mood elevation with ChEI use. Among older patients with neurocognitive disorders (such as the patient presented in this case), there might be subtypes who are particularly vulnerable to activation effects of ChEIs (i.e., those with evidence of vascular pathology and those with mixed — AD and vascular pathology). It is also plausible that a subtype of patients with preexisting clinical or preclinical mood pathology vulnerabilities may have altered neurobiochemical susceptibility causing a paradoxical reaction to heightened levels of acetylcholine associated with donepezil use. Management is based on limited case reports with no clear direction. So far, the literature indicates that discontinuation of ChEI is warranted and a later rechallenge with ChEI may cause recurrence of mania (see Table 1). Although rare, ChEI-associated mania may represent a class effect; thus, switching agents within the ChEI class may not be an option. Switching to memantine, a cognitive enhancer with a different mechanism of action that is generally indicated in moderate to severe (rather
than mild) stages of a major neurocognitive disorder may be a practical alternative since memantine has been shown to have mood stabilizing properties for bipolar patients who failed to respond to standard treatments for mania; thus, it appears to be at low risk for itself inducing mania [31]. Moreover, memantine has been reported to be effective in manic symptoms occurring in psychiatric disorders other than bipolar disorder [31]. However, caution is necessary since new cases of memantine‐induced or worsening psychotic symptoms have also been reported [32,33]. For the management of the manic episode itself, beyond decisions regarding cognitive enhancers, empiric treatment with mood stabilizers and/or atypical antipsychotics (taking into account the usual cautions in using these agents in cognitively and physically vulnerable patients) is indicated, with close observation of mood/psychotic/cognitive symptoms.
4. Conclusion The pathophysiology of donepezil‐induced mania is not well understood and it appears to contradict the traditional cholinergic‐adrenergic hypothesis. Donepezil‐associated mania should be suspected after donepezil initiation or up-titration when temporally correlated to new onset of mania. A manic episode could be elicited by donepezil, alone or a cumulative/additive effect of another medication known to increase the risk for mania (e.g., antidepressant, corticosteroid, immune modulator). Donepezil should be used more cautiously in patients with current or previous mood episodes, particularly bipolar I disorder, or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Management involves discontinuation of donepezil, mood stabilization including treatment with an anticonvulsant or an antipsychotic agent (which is subject to the various cautions in geriatric patients with major neurocognitive disorders), consideration of ECT for treatment-refractory symptoms and/or switch to memantine. Clinicians should be aware of this potential adverse event of donepezil (and implicitly all ChEIs) to result in mood elevation and mania especially as the off‐label use for this drug class increases. With the caveat that this is an area that will require further investigation in different patient populations, there may be subtypes of older patients
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
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with neurocognitive disorders who are particularly vulnerable to activation effects of ChEIs. References [1] Burt T. Donepezil and related cholinesterase inhibitors as mood and behavioral controlling agents. Curr Psychiatry Rep 2000;2:473–8. [2] Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ. A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972;2(7778):632–5. [3] Donepezil hydrochloride. Product monograph. Health Canada. http://webprod5.hcsc.gc.ca/dpd-bdpp/info.do?code=90449&lang=eng. [Accessed May 2, 2015]. [4] Burt T, Sachs GS, Demopulos C. Donepezil in treatment-resistant bipolar disorder. Biol Psychiatry 1999;45:959–64. [5] Eden Evins A, Demopulos C, Nierenberg A, Culhane MA, Eisner L, Sachs G. A doubleblind, placebo-controlled trial of adjunctive donepezil in treatment-resistant mania. Bipolar Disord 2006;8:75–80. [6] Chen J, Lu Z, Zhang M, et al. A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania. Neuropsychiatr Dis Treat 2013;9:839–45. [7] Kelly T. Is donepezil useful for improving cognitive dysfunction in bipolar disorder? J Affect Disord 2008;107(1–3):237–40. [8] Gildengers AG, Butters MA, Chisholm D, Reynolds CF, Mulsant BH. A 12-week openlabel pilot study of donepezil for cognitive functioning and instrumental activities of daily living in late-life bipolar disorder. Int J Geriatr Psychiatry 2008;23(7):693–8. [9] Peet M, Peters S. Drug-induced mania. Drug Saf 1995;12(2):146–53. [10] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–14. [11] Weiner MF, Martin-Cook K, Foster BM, Saine K, Fontaine CS, Svetlik DA. Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry 2000;61:487–92. [12] Mega MS, Masterman DM, O’Connor SM, Barclay TR, Cummings JL. The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol 1999;56:1388–93. [13] Benazzi F. Mania associated with donepezil. Int J Geriatr Psychiatry 1998;13(11): 814–5. [14] Benazzi F. Mania associated with donepezil. J Psychiatry Neurosci 1999;24(5): 468–9.
[15] Benazzi F, Rossi E. Mania and donepezil. Can J Psychiatry 1999;44(5):506–7. [16] Rao V, Ovitt L, Robbins B. Donepezil induced hypomania. J Neuropsychiatry Clin Neurosci 2008;20(1):107. [17] Collins C, Copeland B, Croucher M. Bipolar affective disorder, type II, apparently precipitated by donepezil. Int Psychogeriatr 2011;23(3):503–4. [18] Ehrt U, Fritze F, Aarsland D. Mania after administration of cholinesterase inhibitors in patients with dementia and comorbid bipolar disorder: two case reports. J Clin Psychopharmacol 2011;31(2):254–6. [19] Wicklund S, Wright M. Donepezil-induced mania. J Neuropsychiatry Clin Neurosci 2012;24(3):E27. [20] Tseng WS, Tzeng NS. A rivastigmine-precipitated manic episode in a patient with Alzheimer-type dementia. Int Psychogeriatr 2012;24(10):1697–9. [21] Leung JG. Donepezil-induced mania. Consult Pharm 2014;29(3):191–5. [22] Pompeia S, Gouveia JR, Galduróz JC. Acute mood effect of donepezil in young, healthy volunteers. Hum Psychopharmacol 2013;28(3):263–9. [23] Tourian L, Margolese HC, Gauthier S. Donepezil-associated mania in two patients who were using donepezil without a prescription. J Clin Psychopharmacol 2014; 34(6):753–5. [24] Nivoli AM, Murru A, Goikolea JM, et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord 2012;140(2):125–41. [25] Beyer JL, Young R, Kuchibhatla M, Krishnan KRR. Hyperintense MRI lesions in bipolar disorder: a meta-analysis and review. Int Rev Psychiatry 2009;21(4):394–409. [26] Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003;73(3):170–7. [27] Cacabelos R. Donepezil in Alzheimer’s disease: from conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat 2007;3(3):303–33. [28] Decker MW, McGaugh JL. The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory. Synapse 1991;7(2):151–68. [29] van Enkhuizen J, Geyer MA, Halberstadt AL, Zhuang X, Young JW. Dopamine depletion attenuates some behavioral abnormalities in a hyperdopaminergic mouse model of bipolar disorder. J Affect Disord 2014;155:247–54. [30] Shearman E, Rossi S, Szasz B, et al. Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study. Brain Res Bull 2006;69(2):204–13. [31] Serra G, Demontis F, Serra F, et al. Memantine: new prospective in bipolar disorder treatment. World J Psychiatry 2014;4(4):80–90. [32] Canan F, Ataoglu A. Memantine-related psychotic symptoms in a patient with bipolar disorder. J Clin Psychiatry 2010;71(7):957. [33] Ridha BH, Josephs KA, Rossor MN. Delusions and hallucinations in dementia with Lewy bodies: worsening with memantine. Neurology 2005;65(3):481–2.
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Donepezil-associated manic episode with psychotic features: a case report and review of the literature☆ Ana Hategan, M.D. a,⁎, James A. Bourgeois, O.D., M.D. b a Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada b Department of Psychiatry/Langley Porter Psychiatric Institute, Consultation/Liaison Service, University of California San Francisco Medical Center, San Francisco, CA, USA
a r t i c l e
i n f o
Article history: Received 3 May 2015 Revised 14 September 2015 Accepted 16 September 2015 Available online xxxx Keywords: Donepezil Cholinesterase inhibitors Mania Neurocognitive disorders Dementia
a b s t r a c t Objective: Reports of manic episodes associated with the use of cholinesterase inhibitors (including donepezil) are limited. Despite the previous notion of procholinergic drugs potentially inducing depression, the contemporary evidence for cholinesterase inhibitors appears to also indicate a trend for elevated mood (in patients with or without a history of depressive disorder). Method: Case report. Results: The authors report a case of a manic episode with psychotic features associated with the up-titration of donepezil in a patient with Alzheimer’s disease and a distant history of major depression but without a preexisting bipolar disorder. Conclusion: Pathophysiology of donepezil-induced mania appears to contradict the traditional cholinergicadrenergic hypothesis. Donepezil-associated mania should be suspected after donepezil initiation/dose up-titration when correlated to new onset of mania. Donepezil should be used more cautiously in patients with current or previous mood episodes or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Although this requires further investigation in different patient populations, there may be subtypes of older patients with neurocognitive disorders who are particularly vulnerable to activation effects of cholinesterase inhibitors. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Old anecdotal reports have indicated that exposure to cholinomimetic drugs, such as pilocarpine, physostigmine and organophosphate insecticides, may in fact have a depressogenic or antimanic effect [1]. In 1972, Janowsky et al. [2] postulated the classical cholinergic-adrenergic hypothesis, possibly involving reciprocating and balancing effects of procholinergic agents on mood, in that excess acetylcholine was associated with depression and decreased acetylcholine was associated with mania. According to this hypothesis, cholinesterase inhibitors (ChEIs) such as donepezil approved to treat memory dysfunction in Alzheimer’s disease (AD) [3], should not cause mania unless there are other relevant contributory factors not captured by this explanatory model. This hypothesis led to the study of off-label use of donepezil as an augmentation agent for commonly used mood stabilizers (e.g., lithium
☆ Conflict of Interest and Source of Funding: The authors report no relevant financial relationships and no conflict of interest. ⁎ Corresponding author. Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, St. Joseph’s Healthcare Hamilton, West 5th Campus, 100 West 5th Street, Hamilton ON, Canada L8N 3K7. E-mail address: [email protected] (A. Hategan).
or valproate) for treatment of refractory mania, which has shown mixed results [4–6]. In particular, two double-blind, placebocontrolled studies have failed to show any benefit [5,6]; continuation of therapeutic doses of the primary mood stabilizer was shown to be superior to augmentation with donepezil in one study [5], whereas donepezil had some benefit on the first day but did not provide any significant benefits in the long term in the other study [6]. Moreover, trials of donepezil assessing cognitive dysfunction in patients with bipolar disorder particularly warned of a concerning trend for donepezil to destabilize bipolar I patients [7,8]. Therefore, the previously established notion of increased cholinergic tone being associated with depression (or an antimanic effect) may not be as sound as once hypothesized. Donepezil-related adverse events of mania or hypomania per se were not identified in clinical trials leading to regulatory approval; however, irritability, emotional lability, restlessness, aggression, paranoia and delusions were reported [3]. There are abundant reports in the medical literature of various drug classes reported to induce mania (e.g., antidepressants, corticosteroids, levodopa, thyroxine, chloroquine) [9]. ChEIs have also been studied for their effects on mood and behavior in the treatment of AD-related neuropsychiatric symptoms (NPS) (e.g., apathy, depression, psychosis, sleep disturbance and agitation), which can further impact patients’ performance on instrumental and basic activities of daily living [10]. In this population, donepezil
http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004 0163-8343/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
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has been associated with a mild improvement from baseline for the responders on NPS in AD, including delusions, agitation, anxiety, disinhibition and irritability; these effects were dose dependent [11,12]. Our observations based on the following case description might add to the challenge of the cholinergic-aminergic hypothesis of mood disorders and suggest a need for revising the role of ChEIs in this hypothesis. 2. Case report A 72-year-old Caucasian female with a recent diagnosis of a probable major neurocognitive disorder due to AD was admitted to a psychiatric unit with a 1-month history of increasing cognitive and behavioral disorganization, pressured speech, hyperreligiosity, hypersexuality, delusions, insomnia, agitation and violent behavior. This symptomatology occurred within 1 week of increasing her donepezil from 5 mg to 10 mg daily. Donepezil was suspected to have induced her new NPS and was discontinued 3 days prior to admission. She continued to endorse delusional conviction that her husband had had an affair with a 24-year-old woman with whom he had a 1-year-old son, which aggravated marital discord. The patient disclosed to her daughter that, during the previous night, she had attempted to stab her husband, having put a knife to his chest during his sleep, but then changed her mind and stopped short of physically harming him. This disclosure precipitated admission to the hospital. Her past psychiatric history included a single major depressive episode 8 years previously, which fully remitted on duloxetine 30 mg daily. Her medical history included fibromyalgia, for which duloxetine 30 mg daily had been also used and continued at unchanged dosage. She had hypertension, which was treated with ramipril 2.5 mg daily. Her family psychiatric history included several biological relatives with major depressive disorder. On examination, the patient displayed a marked psychomotor agitation, pressured speech, labile affect (with marked fluctuations of euphoria, irritability and tearfulness), delusions of jealousy and grandiosity, flight of ideas and loosening of associations. She denied any suicidal or homicidal ideation, and there were no hallucinations. Her insight and judgment were impaired. She was alert, oriented to place and disoriented to time. Montreal Cognitive Assessment (MoCA) score was 15 out of 30 on admission. The physical examination and laboratory investigations (including hematologic, electrolyte, renal, hepatic, thyroid and urinalysis parameters) were all normal. Computed tomography of brain revealed patchy, confluent areas of white matter hypoattenuation within the subcortical, periventricular and deep white matter tracts, which were reported as age-related chronic microangiopathic changes. Her daughter was the proxy decision maker for medical treatment. Medication changes upon admission included discontinuation of duloxetine and initiation and up-titration of risperidone to 1.5 mg daily. Donepezil was not restarted. Her fibromyalgia symptoms did not worsen. Her psychiatric symptoms fully remitted within 2 weeks, at which time her mental status examination revealed euthymic affect, goal-directed and coherent thought process, no delusional thinking and no suicidal or homicidal ideation. A repeated MoCA remained stable at 15 out of 30. She was discharged to an outpatient clinic for follow-up and tapering of risperidone dose. At an outpatient visit 10 weeks later, her risperidone had been tapered and completely discontinued and she remained off of psychotropic medication thereafter. Particularly, she was not rechallenged with a cholinesterase inhibitor or duloxetine and was not started on memantine at her and her daughter’s choice. Her mood had remained stable with no recurrence of manic spectrum or psychotic symptoms. 3. Discussion Table 1 describes 11 previously published cases of mania/hypomania associated with ChEIs in the treatment of neurocognitive disorders
(formerly dementia) [13–21]; eight cases alone were associated with donepezil [13–17,19,21]. The existing literature on patients with neurocognitive disorders and ChEI-associated mania does not appear to support vulnerability in any particular subtype of neurocognitive disordered patient to a manic episode; the patients had diagnoses ranging from mild to major neurocognitive disorders of various etiologies (i.e., AD, vascular or repair of a cerebral aneurysm [16]); four patients had personal history of bipolar I disorder and two also had a history of unipolar depression. As illustrated in Table 1, type and daily dose of reported ChEIs varied from donepezil 5 mg (n= 5), donepezil 10 mg (n= 3), galantamine 16 mg (n= 1), rivastigmine 3 mg (n= 1) and rivastigmine 4.6 mg (n=1). Therefore, this adverse event appears to indicate a class effect. The time to manic/hypomanic episode varied from 3 days to 3 weeks from initiation/optimization (dose up-titration) of ChEI. Resolution after ChEI discontinuation, either spontaneously or following treatment with a mood stabilizer and/or antipsychotic, varied from between 1 day to 2 weeks. Donepezil rechallenge resulted in a recurrence of mania in two patients [13–15], whereas rechallenge with a small dose of donepezil was successful in a patient who initially developed mania on rivastigmine [20]. Of concern is some evidence that donepezil could elevate mood even in healthy persons [22,23], which raises potential concerns for misuse. The rapid emergence of psychotic mania in the context of donepezil dose titration in our patient was compelling because of no preexisting history of bipolar disorder including no history of mania induced by duloxetine. This case is similar to previously reported cases of neurocognitive disorders in that the patient presented with a manic episode that commenced within days of up-titrating the donepezil dose. As this case illustrates a plausible contribution of donepezil to the patient’s emergence of mood elevation, a few differential diagnoses are further entertained. Delirium with manic and psychotic features, possibly caused by the combination of medications, might have accounted for elements of this clinical picture. This was felt to be improbable, given the lack of fluctuating level of cognitive status, no altered level of consciousness and no classic inversion of the sleep–wake cycle in this patient; i.e., there was insufficient evidence for a diagnosis of delirium at time of presentation. It is possible that her mood, psychotic and psychomotor manifestations represented distinct expressions of NPS associated with the neurocognitive disorder and not a “primary” bipolar disorder per se. However, treatment with ChEIs in AD patients has in fact demonstrated beneficial effects on NPS, as previously emphasized [10–12]. Intriguingly, the manic and psychotic symptoms in our patient resolved only after discontinuation of donepezil and duloxetine and starting risperidone, an atypical antipsychotic recommended in treatment guidelines for acute bipolar mania [24], thus supporting a plausible causal link to a bipolar diathesis. Based on the neuroimaging findings, a vascular etiology of mood elevation may have been contributory. There is increasing evidence that white matter signal changes, thought to represent areas of ischemic damage to brain tissue, may play an important role in the neurobiology of bipolar disorder, regardless of age [25]. Nevertheless, these lesions are not specific to bipolar disorder but appear at similar rates in unipolar depression and schizophrenia [25]. Therefore, the role of white matter signal changes in the pathogenesis, pathophysiology and response to treatment of manic episodes remains unclear [25]. While ruling out other vulnerability to mania was impossible in this patient, the temporal relationship between the onset of donepezil titration and psychotic mania in this patient suggests the possibility of a causal link. The question remains whether her concomitant use of the antidepressant duloxetine may have played a role. The long-term treatment with antidepressant duloxetine without previous episodes of mania in our patient appeared to favor a new onset, donepezilassociated manic episode rather than a decompensation of a preexisting bipolar diathesis. Both duloxetine and donepezil are mainly metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme, and thus, a cumulative/additive effect of duloxetine and donepezil overburdening this
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
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Table 1 Review of reported cases of cholinesterase inhibitors associated with manic/hypomanic episodes in neurocognitive disorders [13–21]. Authors/year
Reported patients
Benazzi (1998) [13], Benazzi (1999) [14], Benazzi and Rossi (1999) [15]
78 years old F
Rao et al. (2008) [16]
Collins et al. (2011) [17] Ehrt et al. (2011) [18]
Wicklund and Wright (2012) [19] Tseng and Tzeng (2012) [20] Leung (2014) [21]
Medication/ daily dose
Donepezil 5 mg 64 years old F Donepezil 5 mg 68 years old M Donepezil 5 mg 74 years old F Donepezil 10 mg 50 years old M Donepezil 5 mg 76 years old F
Donepezil 10 mg 81 years old F Rivastigmine 4.6 mg patch 76 years old M Galantamine 16 mg 65 years old F Donepezil 5 mg 79 years old M Rivastigmine 3 mg 70 years old M Donepezil 10 mg
Event
Time to event
Time to Rechallenge resolution (after discontinuation of medication)
Cognitive status
Personal and family history of psychiatric disorders
Mania
3–7 days
1–7 days
Mild to severe dementia, unspecified etiology
MDD
Mania
Hypomania
Ø
Mania
Mania
Delusional disorder
Hypomania
Ø
BD type I
Hypomania 3 weeks
Not reported
Ø
BD type I
Hypomania “A few weeks” “Quickly” after dose increase Mania 1 week 1 week
Ø
Cognitive impairment due to cerebral aneurysm repair Vascular dementia
Ø
AD dementia
Minor depressive episodes BD type I
Mania
Family history of BD and MDD
2 weeks
Ø
AD dementia
BD type I
Mania
9 days after dose increase 5 days
Not reported
Ø
Vascular dementia
None
Mania
3 days
2 days
AD dementia
None
Mania
“Days” after dose 2 weeks increase
No mania with donepezil 2.5 mg Ø
Mild cognitive impairment
Paranoid schizophrenia, alcohol dependence
Notes: Ø, no rechallenge; BD, bipolar disorder; F, female; MDD, major depressive disorder; M, male.
metabolic pathway, resulting in increased medication level of one/both of these agents, was impossible to rule out [26,27]. Given the large degree of CYP2D6 phenotypic variation, it would be important to mention that approximately 20% of the AD population may exhibit an abnormal metabolism of ChEIs (including donepezil), of which 50% of this group (i.e., 10% of the total AD population) may be hypometabolizers and therefore increasing the potential for adverse events due to ChEI toxicity [27]. It remains unclear by what mechanism donepezil can induce mania. One mechanistic hypothesis could be that an increase in acetylcholine leads to changes in neurotransmitters and neuromodulators, including dopamine, norepinephrine and serotonin [28]. In animal studies, in which manic-like behavior was explained by a hyperdopaminergic mouse model of bipolar disorder [29], acute administration of donepezil was found to be associated with (a) increase in extracellular dopamine in the cortex and dorsal hippocampus of the treated rodents, (b) increase in norepinephrine in the dorsal hippocampus and the medial temporal cortex and decreased in the ventral hippocampus and (c) decrease in serotonin levels [30]. Further investigation of the monoamine pathways plausibly implicated and comparisons among healthy young adults, cognitively intact older adults and older adults with neurocognitive disorders could identify subtypes of patients who may be particularly vulnerable to activation/mood elevation with ChEI use. Among older patients with neurocognitive disorders (such as the patient presented in this case), there might be subtypes who are particularly vulnerable to activation effects of ChEIs (i.e., those with evidence of vascular pathology and those with mixed — AD and vascular pathology). It is also plausible that a subtype of patients with preexisting clinical or preclinical mood pathology vulnerabilities may have altered neurobiochemical susceptibility causing a paradoxical reaction to heightened levels of acetylcholine associated with donepezil use. Management is based on limited case reports with no clear direction. So far, the literature indicates that discontinuation of ChEI is warranted and a later rechallenge with ChEI may cause recurrence of mania (see Table 1). Although rare, ChEI-associated mania may represent a class effect; thus, switching agents within the ChEI class may not be an option. Switching to memantine, a cognitive enhancer with a different mechanism of action that is generally indicated in moderate to severe (rather
than mild) stages of a major neurocognitive disorder may be a practical alternative since memantine has been shown to have mood stabilizing properties for bipolar patients who failed to respond to standard treatments for mania; thus, it appears to be at low risk for itself inducing mania [31]. Moreover, memantine has been reported to be effective in manic symptoms occurring in psychiatric disorders other than bipolar disorder [31]. However, caution is necessary since new cases of memantine‐induced or worsening psychotic symptoms have also been reported [32,33]. For the management of the manic episode itself, beyond decisions regarding cognitive enhancers, empiric treatment with mood stabilizers and/or atypical antipsychotics (taking into account the usual cautions in using these agents in cognitively and physically vulnerable patients) is indicated, with close observation of mood/psychotic/cognitive symptoms.
4. Conclusion The pathophysiology of donepezil‐induced mania is not well understood and it appears to contradict the traditional cholinergic‐adrenergic hypothesis. Donepezil‐associated mania should be suspected after donepezil initiation or up-titration when temporally correlated to new onset of mania. A manic episode could be elicited by donepezil, alone or a cumulative/additive effect of another medication known to increase the risk for mania (e.g., antidepressant, corticosteroid, immune modulator). Donepezil should be used more cautiously in patients with current or previous mood episodes, particularly bipolar I disorder, or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Management involves discontinuation of donepezil, mood stabilization including treatment with an anticonvulsant or an antipsychotic agent (which is subject to the various cautions in geriatric patients with major neurocognitive disorders), consideration of ECT for treatment-refractory symptoms and/or switch to memantine. Clinicians should be aware of this potential adverse event of donepezil (and implicitly all ChEIs) to result in mood elevation and mania especially as the off‐label use for this drug class increases. With the caveat that this is an area that will require further investigation in different patient populations, there may be subtypes of older patients
Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004
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Please cite this article as: Hategan A, Bourgeois JA, Donepezil-associated manic episode with psychotic features: a case report and review of the literature, Gen Hosp Psychiatry (2015), http://dx.doi.org/10.1016/j.genhosppsych.2015.09.004