See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/341410400

Importance of Distinguishing Reactive and Proactive Aggression in Dementia

Care

Article  in  Journal of Geriatric Psychiatry and Neurology · May 2020

DOI: 10.1177/0891988720924706

CITATION READS

1 293

1 author:

Ladislav Volicer
University of South Florida
431 PUBLICATIONS   16,224 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Namaste View project

Launching Namaste Care, a hospice-like program for people with advanced dementia View project

All content following this page was uploaded by Ladislav Volicer on 21 May 2020.

The user has requested enhancement of the downloaded file.

Commentary
Journal of Geriatric Psychiatry
and Neurology
Importance of Distinguishing Reactive 1-5
ª The Author(s) 2020
Article reuse guidelines:
and Proactive Aggression in Dementia Care sagepub.com/journals-permissions
DOI: 10.1177/0891988720924706
journals.sagepub.com/home/jgp

Ladislav Volicer, MD, PhD1,2

Abstract
Aggressive behavior is one of the most disturbing symptoms of Alzheimer disease and other progressive neurodegenerative
dementias. Development of strategies for management of aggressive behaviors in people with dementia is hindered by a lack of
recognition that aggression is not a uniform behavioral construct. It is possible to distinguish 2 types of aggression: reactive or
impulsive aggression and proactive or premeditated aggression. Research concerning aggressive behaviors in people with
dementia is hindered by scales describing behavioral symptoms of dementia which do not distinguish between reactive and
proactive aggressions because they do not consider the factors leading to these behaviors. Reactive aggression is caused by lack of
understanding, leading to rejection of care, while proactive aggression could be caused by a psychopathic personality, halluci-
nations or delusions, and other determinants. It is difficult to underestimate the importance of distinguishing reactive and
proactive aggressions in people with dementia because there are different strategies that can be used for management of these
behaviors. For reactive aggression, delayed treatment, distraction, improved communication, and change in treatment strategy is
useful, while antipsychotic medication may be needed for treatment of proactive aggression. Dementia is increasing the risk of
both types of aggressions and antidepressant treatment can be helpful. Most importantly, persons exhibiting reactive aggression
should not be labeled “aggressors” because this behavior could be caused by unmet persons’ needs, pain and poor communication
with care providers.

Keywords
agitation, Alzheimer disease, aggression, behavioral therapy, dementia

Behavioral symptoms of dementia are often as important as the
cognitive deficits. They cause distress for patients and their
caregivers, decrease the quality of life of the patients, and may
precipitate caregivers’ depression and anxiety.1 Aggressive
behavior is one of the most disturbing symptoms of Alzheimer
disease (AD) and other progressive neurodegenerative demen-
tias for 2 reasons. First, it may lead to injuries of people with
dementia or their care providers and is often a reason for insti-
tutionalization.2 Second, aggressive behavior is often used as a
reason for administration of dangerous antipsychotic or other
psychoactive medications. Development of strategies for the
management of aggressive behaviors in people with dementia
is hindered by a lack of recognition that aggression is not a
uniform behavioral construct. It is possible to distinguish 2
types of aggression: reactive or impulsive aggression and
proactive or premeditated aggression.
Reactive aggression is considered to be an aggressive
response to a perceived threat or provocation, while proactive
aggression is defined as planned antisocial behavior that antici-
pates a reward or dominance over others.3 Several studies
investigated features of these 2 aggression types in children
and adolescents, but their results are applicable also to
dementia care.
Evidence for the distinction between reactive and proactive
aggression in children was reviewed by Kempes et al.4 This
concept was further supported by results of a study including
66 adolescents with conduct disorder, who completed question-
naire for characterizing aggression. A principal component
analysis of this questionnaire demonstrated 2 stable factors of
aggression with good internal consistency and construct valid-
ity.5 Additionally, when reactive–proactive aggression ques-
tionnaire was administered to over 5000 school children,
confirmatory factor analysis demonstrated a good fit of the 2-
factor reactive–proactive model.6 Results of this study showed
that proactive aggression increased significantly with age in
boys but not in girls, while reactive aggression showed no
gender differences and only a minimal age increase.
1
School of Aging Studies, University of South Florida, Tampa, FL, USA
2
3rd Medical Faculty, Charles University, Prague, Czech Republic
Received 9/30/2019. Received revised 12/26/2019. Accepted 3/15/2020.
Corresponding Author:
Ladislav Volicer, School of Aging Studies, University of South Florida, Tampa, FL,
USA; 3rd Medical Faculty, Charles University, Prague 110 000, Czech Republic.
Email: lvolicer@usf.edu
2 Journal of Geriatric Psychiatry and Neurology XX(X)
Research concerning aggressive behaviors in people with
dementia is hindered by scales describing behavioral symptoms
of dementia which do not distinguish between reactive and
proactive aggressions.7 The Neuropsychiatric Inventory8 asks
in one of the elements “Does the resident have periods when
he/she refuses to let people help him/her? Is he/she hard to
handle? Is he/she noisy or uncooperative? Does the resident
attempt to hurt or hit others?” A positive answer to this ques-
tion may indicate the presence of reactive aggression, which
was provoked by rejection of care, but positive response to the
last question could also indicate the presence of proactive
aggression that was not invoked by the rejection of care. In
addition, the element is confusingly labeled as agitation/
aggression, without acknowledging that agitation and aggres-
sion are 2 different symptoms.8 A scale, which clearly docu-
ments the context of an aggressive behavior is the Staff
Observation Aggression Scale.9,10
Reactive Aggression in Dementia
Ryden and her coworkers provided one of the first detailed
information about the aggression of nursing home residents
with dementia.11 They followed 124 residents on units for the
cognitively impaired in 4 nursing homes over a period of 7 days.
Using the Ryden Aggression Scale, they found that 86% of
these residents showed some form of aggressive behavior; phy-
sically aggressive in 51%, verbally aggressive in 48% and
sexually aggressive in 4% of the incidents. For almost all of
the incidents, an antecedent event was identified, with 72%
involving touching or invasion of personal space during care-
giving, 26% involving staff, other residents or mealtime activ-
ities, and with only 2% for which there was no antecedent
identified. Staff were the primary targets of the behavior (in
87% of incidents) while other residents were targets in 12% and
visitors rarely in 1% of the incidents. These results indicate that
almost all incidents were caused by reactive aggression.
Similarly, analysis of minimum data set (MDS) showed that
resistiveness to care was one of the strongest determinants of
behaviors directed toward others12 and, therefore, these beha-
viors were reactive aggression.
It is unfortunate that 20 years after these publications, nur-
sing assistant still experience high level of aggressive behavior
during personal care as described in a Canadian study.13 The
most disturbing aspect of this report was that the nursing assis-
tant did not know what to do to prevent aggressive behavior and
thought that they just must bear it. They are not told that it is
possible to prevent reactive aggression by changing risk factors
that are causing it (Table 1).14
The first factor is a lack of understanding of caregivers’
intentions and of the need for a care intervention, which results
in rejection of care.15 Therefore, improved communication, both
verbal and non-verbal, may decrease rejection of care. The type
of communication is also important because communication is
not promoted by using infantilizing form (Elderspeak).
Decreased use of elderspeak led to a significant decline in resis-
tiveness to care.16 There is also some indication that culture-
Table 1. Differences Between Reactive and Proactive Aggression.
Aggression Reactive Proactive
Causes Lack of understanding Psychopathic personality
ò
Rejection of care
Hallucinations
Delusions
Depression
Treatments Delayed treatment, distraction Antipsychotic
Improved communication medications
Change in treatment strategy
Non-pharmacological treatment of depression
Antidepressants
Augmentation of antidepressant effect by antipsychotics
appropriate communication decreases behavioral symptoms of
dementia.17 Important is also the tone of the communication
because controlling tone increases incidence of resistiveness to
care.18 An educational program, trying to enhance communica-
tion in nursing home dementia care, increased person-centered
communication by staff and resulted in reduced resistiveness to
care and in decreased use of antipsychotics.19
The second factor is the care that is being provided. A resi-
dent may resist the type of care that he/she is not used to, for
example, shower bath. This situation can be managed by 2 ways:
either by changing the type of care or by making the care more
enjoyable.14 Bed bath may be substituted for shower or tub bath
which the resident resist. The bath can be made more enjoyable
by providing pleasant touch outside of a bath activity, which
makes resident used to touch required for the care. Six weeks
of tactile massage decreased significantly both the
“aggressiveness” score and stress levels of residents with
dementia.20 Another study found that massage with added aroma
was effective in decreasing overall agitation in residents with
dementia but not specifically a rejection of care.21 Caregivers
reported that regular hand massage, provided as a part of
Namaste Care, improved tactility of residents and decreased
significantly their rejection of care during bathing and other care
activities.22 Hand massage and gentle touch can be also provided
by informal care providers including family visitors and this
activity may increase the quality of their visits.23
Ryden and Feldt24 suggested that achieving 5 goals of care
could prevent or reduce aggressive behavior: (1) make resi-
dents to feel safe, (2) make them physically comfortable, (3)
allow them to experience a sense of control, (4) provide an
optimal stress, and (5) make them to experience pleasure. Edu-
cation program for the staff using these principles resulted in
nursing assistants reporting that caring for cognitively impaired
residents was more rewarding and less frustrating.25
Proactive Aggression in Dementia
Occurrence of proactive aggression initiated by a person with
dementia is very rare. Proactive aggression requires intact
Volicer
executive function for planning of this behavior, and executive
function is impaired in most types of dementia. A survey of
dementia patients who had been in trouble with the law found
22 patients who committed proactive, mostly non-violent,
sociopathic acts; for example, disinhibited sexual behavior or
pathological stealing.26 These aggressive patients had mostly
frontally predominant illnesses, such as frontotemporal demen-
tia or Huntington disease, and the common mechanism was
disinhibition. Some proactive aggression was also found during
investigation of aggression between residents, but for most of
these behaviors, it was possible to identify a trigger.27
Evaluation of aggressive behavior in psychogeriatric inpa-
tients found in 12 months shows 146 incidents involving 66
patients.28 In 20% of these incidents, no precipitating event
could be identified and, therefore, the incident could be con-
sidered a proactive aggression. Proactive aggressions were sig-
nificantly more common in patients without dementia (25% of
incidents) than in patients with dementia (12% of the inci-
dents). Nurses were significantly more often the target of
aggression involving patients with dementia (in 83% of inci-
dents) than in incidents involving patients without dementia (in
61% of incidents). This indicates that most aggressive incidents
involving patients with dementia occurred during nursing care
activities and was reactive aggression.
Aggression and Depression
Depression was found to be related to aggression in many
studies.29 For instance, irritability as a symptom of depression
is related to domestic violence and in a college sample, there
was a correlation between depression and by both verbal and
physical hostility.30 It is interesting that gender differences
were found in the relationship between depression and the type
of aggression with depressed females being more verbally
aggressive while depressed males were more likely physically
aggressive.31 According to my clinical experience, there is
similar gender difference in the type of aggression in persons
with dementia.
Prevalence of depression diagnoses in nursing home resi-
dents ranges from 11% to as high as 78%.32 One reason for
highly variable prevalence rates of depression is the difficulty
of diagnosing depression in residents with cognitive impair-
ment, due to AD and other progressive dementias, who often
constitute the majority of nursing home residents. Major over-
lap between symptoms of depression and symptoms of demen-
tia complicate accurate diagnosis.33 Furthermore, disagreement
over diagnostic criteria for depression in AD is another reason
why prevalence rates are so variable; no general consensus on
the most valid method to assess and to diagnose depression in
AD exists.33
High prevalence of depression in individuals with AD might
be expected because AD causes serotoninergic deficit34 that
may be involved in the pathogenesis of depression. Some data
indicate that serotoninergic deficit may be related to aggressive
behaviors. There is a clear association between low cerebrosp-
inal fluid serotonin and impulsive aggression.35 In addition,
3
individuals are predisposed to reactive aggression if they have
low functioning monoamine oxidase A genotype because they
have the tendency to act impulsively in the context of negative
effect.36 In patients with AD, density of 5-HT1A receptors
determined on autopsy was lower in patients exhibiting aggres-
sion before death indicating that they had lower serotoninergic
activity.37 The relationship between serotoninergic function
and aggressive behavior may not be unique for AD because
endogenous serotonin deficiency was found also in frontotem-
poral dementia, and treatment with a selective serotonin reup-
take inhibitor citalopram was effective in decreasing
behavioral disturbances.38
Minimum data set, presented by nursing home staff, pro-
vides information about aggressive behaviors, labeled as beha-
viors directed toward others. Analysis of MDS data has shown
that the 2 most important factors for occurrence of aggressive
behavior were lack of understanding and rejection of care.
Depression contributed to both rejection of care and behaviors
directed toward others and the relationship between depression
and behaviors toward others was mediated not only by rejection
of care but also by depression alone.12 In only 4% of the inci-
dents, there was no rejection of care or depression present.
These results suggest that antidepressants should be the first
line of medication for individuals exhibiting abusive behavior
if psychotic symptoms are not present, and nonpharmacologi-
cal strategies are ineffective.39
Symptoms of depression may be improved by distraction or
cheering up40 and by involvement in meaningful activities.41,42
If these interventions fail to decrease depression, antidepres-
sants may be required. Although some studies found improve-
ment of behavioral symptoms after treatment with
antidepressants,43,44 other studies were negative. This was
probably due to insufficient doses and duration of treatment.
This was documented by the depression in AD study which
found that treatment with sertraline decreased behavioral dis-
turbances and caregiver distress only in patients whose depres-
sion responded to antidepressant treatment39 Antidepressant
treatment was found effective in decreasing behavioral symp-
toms of dementia by a Cochrane data analysis.45 but antide-
pressants may sometimes require augmentation with atypical
antipsychotics.46
Use of antidepressants is sometimes avoided because of fear
of side effects, reported by a population cohort study.47 How-
ever, a meta-analysis involving 19 randomized controlled trials
and 2 observational studies found statistically similar frequen-
cies of overall adverse events in placebo- and selective seroto-
nin release inhibitors-treated patients, but serotonin and
norepinephrine selective inhibitors caused more overall
adverse events than placebo. Duloxetine led to more falls than
placebo during 24 weeks of acute and continuation treatment.48
Conclusions
It is difficult to underestimate the importance of distinguishing
reactive and proactive aggressions in people with dementia
because there are different strategies that can be used for
4 Journal of Geriatric Psychiatry and Neurology XX(X)
management of these behaviors. The precipitating factor needs
to be considered for recognition of the difference between these
2 behaviors. Most importantly, persons exhibiting reactive
aggression should not be labeled “aggressors” because that is
blaming victims of inappropriately provided care. Treatment of
proactive aggression will require development and approval of
safe antipsychotics. Reactive aggression should be prevented
by improved communication and modification of nursing stra-
tegies. More research is needed to discover strategies that will
be implemented easily and will not increase workload of the
staff.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Ladislav Volicer https://orcid.org/0000-0002-6939-7531
References
1. Radue R, Walaszek A, Asthana S. Neuropsychiatric symptoms in
dementia. Handb Clin Neurol. 2019;167:437-454.
2. Brodaty H, Low LF. Aggression in the elderly. J Clin Psychiatry.
2003;64:36-43.
3. Waltes R, Chiocchetti AG, Freitag CM. The neurobiological basis
of human aggression: A review on genetic and epigenetic
mechanisms. Am J Med Genet B Neuropsychiatr Genet. 2016;
171(5):650-675.
4. Kempes M, Matthys VV, de Vries H, van Engeland H. Reactive
and proactive aggression in children—a review of theory, findings
and the relevance for child and adolescent psychiatry. Eur Child
Adolesc Psychiatry. 2005;14(1):11-19.
5. Mathias CW, Stanford MS, Marsh DM, et al. Characterizing
aggressive behavior with the impulsive/premeditated aggression
scale among adolescents with conduct disorder. Psychiatry Res.
2007;151(3):231-242.
6. Fung AI, Raine A, Gao Y. Cross-cultural generalizability of the
reactive-proactive aggression questionnaire (RPQ). J Pers Assess.
2009;91(5):473-479.
7. Volicer L, Citrome L, Volavka J. Measurement of agitation and
aggression in adult and aged neuropsychiatric patients: review of
definitions and frequently used measurement scales. CNS Spectr.
2017;22(5):407-414.
8. Cummings JL, Mega M, Gray K, Thompson SR, Carusi DA,
Gombert J. The neuropsychiatric inventory: comprehensive
assessment of psychopathology in dementia. Neurology. 1994;
44(12):2308-2314.
9. Nijman H, Palmstierna T. Measuring aggression with the staff
observation aggression scale–revised. Acta Psychiatr Scand.
2002;(412):101-102.
10. Nijman HL, Palmestiema T, Almvik R, Stolker JJ. Fifteen years
of research with the staff observation aggression scale: a review.
Acta Psychiatr Scand. 2005;111(1):12-21.
11. Ryden MB, Bossenmaier M, McLachlan C. Aggressive behavior
in cognitively impaired nursing home residents. Res Nurs Health.
1991;14(2):87-95.
12. Garre FG, Volicer L, Van der Steen JT. Factors related to rejec-
tion of care and behaviors directed towards others: a longitudinal
study in nursing home residents with dementia. Dement Geriatr
Cogn Dis Extra. 2015;5(1):123-134.
13. Morgan DG, Cammer A, Stewart NJ, et al. Nursing aids reports of
combative behavior by residents with dementia: results form a
detailed prospective diary. J Am Med Dir Assoc 2012;13(3):
220-227.
14. Sloane PD, Honn VJ, Dwyer SAR, Wieselquist J, Cain C, Meyers
S. Bathing the Alzheimer’s patient in long term care. Results and
recommendations from three studies. Am J Alzheimer’s Dis. 1995;
10:3-11.
15. Volicer L, Bass EA, Luther SL. Agitation and resistiveness to care
are two separate behavioral syndromes of dementia. J Am Med
Dir Assoc. 2007;8(8):527-532.
16. Williams KN, Perkhounkova Y, Herman R, Bossen A. A com-
munication intervention to reduce resistiveness in dementia care:
a cluster randomized controlled trial. Gerontologist. 2017;57(4):
707-718.
17. Kim H, Woods DL, Mentes JC, Martin JL, Moon A, Phillips LR.
The nursing assistants’ communication style and the behavioral
symptoms of dementia in Korean-American nursing home resi-
dents. Geriatr Nurs. 2014;35(2 suppl): S11-S16.
18. Williams KN, Herman RE. Linking resident behavior to dementia
care communication: effects of emotional tone. Behav Ther 2011;
42(1):42-46.
19. Shaw C, Williams KN, Perhounkova Y. Educating Nursing home
staff in dementia sensitive communication: impact on antipsycho-
tic medication use. J Am Med Dir Assoc. 2018;19(12):1129-1132.
20. Suzuki M, Tatsumi A, Otsuka T, et al. Physical and psychological
effects of 6-week tactile massage on elderly patients with severe
dementia. Am J Alzheimer’s Dis Other Demen. 2010;25(8):
680-686.
21. Yang YP, Lee PP, Chao HC, Hsu FY, Wang JJ. Comparing the
effects of cognitive stimulation, reminiscence, and aroma-
massage on agitation and depressive mood in people with demen-
tia. J Am Med Dir Assoc. 2016;17(8):719-724.
22. Manzar BA, Volicer L. Effects of namaste care: pilot study. Am J
Alzheimer’s Dis. 2015;2:24-37.
23. Hulme C, Wright J, Crocker T, Oluboyede Y, House A. Non-
pharmacological approaches for dementia that informal carers
might try or access: a systematic review. Int J Geriatr Psychiatry.
2010;25(7):756-763.
24. Ryden MB, Feldt KS. Goal-directed care: caring for aggressive
nursing home residents with dementia. J Gerontol Nurs. 1992;
18(11):35-42.
25. Feldt KS, Ryden MB. Aggressive behavior. Educating nursing
assistants. J Gerontol Nurs. 1992;18(5):3-12.
26. Mendez MF, Shapira JS, Saul RE. The spectrum of sociopathy in
dementia. J Neuropsychiatry Clin Neurosci. 2011;23(2):132-140.
Volicer
27. Caspi E. Aggressive behaviors between residents with dementia
in an assisted living residence. Dementia. 2015;14(4):528-546.
28. Paschali M, Kamp D, Reichmann C, Jaenner M, Aschenfeldt CL,
Supprian T. A systematic evaluation of impulsive-aggressive
behavior in psychogeriatric inpatients using the staff observation
aggression scale revision (SOAR-R). Int Psychogeriatr. 2018;
30(1):61-68.
29. Mayrueix L, Durham G, Miller J, Smalley KB, Warren JC. Asso-
ciation between depression and aggression in rural women.
J Health Dispar Res Pract. 2015;8(4):136-144.
30. Johnston V, Rodgers A, Searight H. The relationship between
overt hostility, covert hostility and depression. J Social Behav
Personal. 1991;6(1):85-92.
31. Roberts S, Glod CA, Kim R, Hounchell J. Relationships between
aggression, depression, and alcohol, tobacco: implications for
healthcare providers in student health. J Am Acad Nurse Pract.
2010;22(7):369-375.
32. Gaboda D, Lucas J, Siegel M, Kalay E, Crystal S. No longer
undertreated? Depression diagnosis and antidepressant therapy
in elderly long-stay nursing home residents, 1999 to 2007. J Am
Geriatr Soc. 2011;59(4):673-680.
33. Starkstein SE, Mizrahi R, Power BD. Depression in Alzheimer’s
disease: phenomenology, clinical correlates and treatment. Int
Rev Psychiatry. 2008;20(4):382-388.
34. Yamamoto T, Hirano A. Nucleus raphe dorsalis in Alzheimer’s
disease: neurofibrillary tangles and loss of large neurons. Ann
Neurol. 1985;17(6):573-577.
35. Glick AR. The role of serotonin in impulsive aggression, suicide,
and homicide in adolescents and adults: a literature review. Int J
Adolesc Med Health. 2015;27(2):143-150.
36. Chester DS, DeWall CN, Derefinko KJ, et al. Monoamine oxidase
A (MAOA) genotype predicts greater aggression through impul-
sive reactivity to negative affect. Behav Brain Res. 2015;283:
97-101.
37. Lai MKP, Tsang SWY, Francis PT, et al. Reduced serotonin 5-HT1A
receptor binding in the temporal cortex correlates with aggressive
behavior in Alzheimer disease. Brain Res. 2003;974(1-2):82-87.
38. Herrmann N, Black SE, Chow T, Cappell J, Tang-Wai DF, Lanc-
tot KL. Serotonergic function and treatment of behavioral and
View publication stats
5
psychological symptoms of frontotemporal dementia. Am J Ger-
iatr Psychiatry. 2012;20(9):789-797.
39. Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depres-
sion in Alzheimer disease: efficacy and safety of sertraline ther-
apy, and the benefits of depression reduction: the DIADS. Arch
Gen Psychiatry 2003;60(7):737-746.
40. Merriam AE, Aronson MK, Gaston P, Wey SL, Katz I. The psy-
chiatric symptoms of Alzheimer’s disease. JAGS. 1988;36(1):
7-12.
41. Vance DE, Moore BS, Farr KF, Struzick T. Procedural memory
and emotional attachment in Alzheimer disease: implications for
meaningful and engaging activities. J Neurosci Nurs. 2008;40(2):
96-102.
42. Mansfield JC, Marx MS, Ali MD, Regier NG, Thein K, Freedman
L. Can agitated behavior of nursing home residents with dementia
be prevented with the use of standardized stimuli? J Am Geriatr
Soc. 2010;58(8):1459-1464.
43. Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T.
A randomized, placebo-controlled study of the efficacy and safety
of sertraline in the treatment of the behavioral manifestations of
Alzheimer’s disease in outpatients treated with donepezil. Int J
Geriatr Psychiatry. 2004;19(1):9-18.
44. Pollock BG, Mulsant BH, Rosen J, et al. Comparison of citalo-
pram, perphenazine, and placebo for the acute treatment of psy-
chosis and behavioral disturbances in hospitalized, demented
patients. Am J Psychiatry 2002;159(3):460-465.
45. Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P.
Antidepressants for agitation and psychosis in dementia.
Cochrane Database Syst Rev. 2011;16(2):CD008191.
46. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of
antidepressants with atypical antipsychotic medications for
treatment-resistant major depressive disorder: a meta-analysis.
J Clin Psychiatry. 2007;68(6):826-831.
47. Coupland C, Dhiman P, Morriss R, Antony A, Garry B, Hippisley
CJ. Antidepressant use and risk of adverse outcomes in older
people: population based cohort study. Br Med J. 2011;343:1-15.
48. Sobieraj DM, Martinez BK, Hernandez AV, et al. adverse effects
of pharmacologic treatments of major depression in older adults.
J Am Geriatr Soc. 2019;67(8):1571-1581.