718810

case-report2017
TPP0010.1177/2045125317718810Therapeutic Advances in PsychopharmacologyC. Smart et al.

Therapeutic Advances in Psychopharmacology Case Report

Acetylcholinesterase inhibitors in
Ther Adv Psychopharmacol

2018, Vol. 8(1) 59­–61

treatment-resistant psychotic depression DOI: 10.1177/

https://doi.org/10.1177/2045125317718810
https://doi.org/10.1177/2045125317718810
2045125317718810

© The Author(s), 2017.

Reprints and permissions:
Chris Smart, Hamish McAllister-Williams and David Andrew Cousins http://www.sagepub.co.uk/
journalsPermissions.nav

Abstract:  Dopamine receptor antagonists can be effective in psychotic depression but

response is not assured. Visual hallucinations may arise from a dysregulation of brain
cholinergic systems and acetylcholinesterase inhibitors (AChEIs) can treat such hallucinations
in dementia with Lewy bodies (DLB). AChEIs have been used in schizophrenia with some
success but their efficacy and tolerability in psychotic depression is unclear. This striking case
illustrates AChEIs specifically targeting multimodal hallucinations in treatment-resistant
depression. To our knowledge it is the first case report to do so. It highlights the value of
delineating psychopathology when considering novel interventions. This case also shows the
idiosyncratic nature of side effects and the importance of pursuing different drugs within
class.

Keywords:  acetylcholinesterase inhibitors, multimodal hallucinations, psychotic depression,

treatment resistance

Received: 6 June 2017; revised manuscript accepted: 8 June 2017

Case report In July 2012, he was admitted electively during

Mr M, a 53-year-old White man, had a 25-year maintenance ECT (135 bilateral stimulus deliv-
history of recurrent, refractory psychotic depres- eries) whilst taking nortriptyline (300 mg daily),
sion (World Health Organization ICD-10 revi- amisulpride (300 mg daily), chlorpromazine (300
sion F33.3) that necessitated over 30 hospital mg daily) and lamotrigine (100 mg daily). ECT
admissions. Identifiable triggers were lacking and caused marked cognitive impairment but when
remission rarely achieved. Excepting childhood stopped, in November 2012, his psychotic depres-
anxiety, he was well adjusted before first presen- sion worsened. He described – with horror – see-
tation. Drug or Alcohol misuse did not feature. ing and hearing a “foul-smelling dark man” and
Treatments of adequate dose and duration could not understand why others did not. This
included: antidepressants from every major class, multimodal hallucination was mood congruent,
alone and in combination; lithium and carba- and involved threats to kill the patient’s family Correspondence to:
Chris Smart
mazepine augmentation; antipsychotics (first and unless he committed suicide. He often mistook Academic Psychiatry,
second generation, oral and parenteral) includ- the ward for his home, required physical contact Wolfson Research Centre,
Campus for Ageing
ing clozapine, which was stopped due to neutro- to ensure that staff were ‘real’ and had vivid and Vitality, Newcastle
penia; numerous electroconvulsive therapy dreams of being burned or drowned. University, Newcastle
upon Tyne, NE4 5PL, UK
(ECT) courses, approximating 600 stimulus Chris.Smart@newcastle.
deliveries; psychosurgery twice (bilateral anterior Rivastigmine was prescribed (4.2 mg/day trans- ac.uk
Hamish McAllister-
capsulotomy in 1996 and anterior cingulotomy dermal patch) off-licence in January 2013. His Williams
in 1999), both producing unsustained responses. hallucinations lessened and resolved fully within a David Andrew Cousins
Regional Affective
Postsurgical absence seizures responded to lamo- month; his mood improved concurrently. Drugs Disorders Service,
trigine, but his depression did not. He remained with anticholinergic properties were withdrawn Northumberland Tyne and
Wear NHS Foundation
out of hospital periodically with the support during this period. Regrettably, intolerable side Hospital Trust, Newcastle
of his family and a combination of regular medi- effects emerged: sialorrhoea, uncontrolled by upon Tyne, UK, and
Institute of Neuroscience,
cation, as required chlorpromazine and mainte- hyoscine or ipratropium bromide 0.03% spray, Newcastle University,
nance ECT. resulted in aspiration pneumonia. Donepezil Newcastle upon Tyne, UK

journals.sagepub.com/home/tpp 59
Therapeutic Advances in Psychopharmacology 8(1)
(10 mg daily) was prescribed in May 2013 and
although the drug was better tolerated, his hallu-
cinations and low mood remained. In August, riv-
astigmine was re-started with a view to countering
sialorrhoea as early as possible with oral ipratro-
pium bromide. This worked well but the patient
requested a medication change due to oral pain,
headache and nausea unresponsive to increased
regular chlorpromazine. In November 2013
the N-methyl-D-aspartate receptor antagonist
memantine (up to 20 mg once daily) was pre-
scribed but, despite an initial improvement in
symptoms, there was a suboptimal response after
a 10-week trial. Galantamine (4 mg daily) was
then prescribed and tolerated with good thera-
peutic effect in January 2014 and the patient was
discharged home within a month. Other than
brief episodes of mild depression he remained
largely symptom free for 18 months, whilst pro-
gressively withdrawing chlorpromazine, but sub-
sequently relapsed despite increasing galantamine
to 8 mg daily. He was switched to rivastigmine for
2 weeks and responded. Following symptom res-
olution (and the emergence of sialorrhoea) he was
returned to maintenance galantamine. He has
since remained in partial remission. (The patient
provided written informed consent for his case to
be written up and published in a peer-reviewed
journal.)
Discussion
Response rates to dopamine receptor antagonists
in psychotic depression are suboptimal.1 Whilst
favourable results have emerged for AChEIs in
schizophrenia,2 their efficacy and tolerability in
psychotic depression remain opaque. Our patient
experienced marked therapeutic and adverse
effects with AChEIs. Dysregulated brain cholin-
ergic systems have been suggested to lead to vis-
ual hallucinations3 which AChEIs can treat
effectively in DLB.4 However, our patient’s
response is unlikely to be due to an underlying
DLB, as his presentation was stable over decades
without overt parkinsonism and cognition was
preserved on recovery. Furthermore his adverse
effects were more marked than usual in DLB,
perhaps reflecting a different underlying patho-
physiology. The resolution of hallucinations is
likely attributable to procholinergic effects along-
side incremental improvements from the removal
of anticholinergic drugs, although his partial
response to chlorpromazine and clozapine count
against this. There is a relative dearth of evidence
60 journals.sagepub.com/home/tpp
for the effectiveness of AChEIs in psychosis and
the studies that have been conducted5,6 have
not investigated multimodal hallucinations.
Xanomeline, a selective muscarinic receptor
agonist, has been associated with significant
improvements in Positive and Negative Syndrome
Scale (PANSS) scores compared with placebo.7
Meanwhile, a Cochrane review2 demonstrated
benefit from acetylcholinesterase inhibitors versus
placebo when added to antipsychotics in patients
with schizophrenia. Both PANSS and depressive
symptom scores improved but findings were lim-
ited by the small number of studies. AChEIs have
been trialled in the elderly with mild cognitive
impairment and depression, hypothesizing that
improving cognition would improve mood but
finding that fewer patients entered remission.8
However, this trial did not specifically examine
visual hallucinations in those with depression.
Targeting cholinergic systems could be a future
avenue for visual hallucinations in affective disor-
ders, but clinicians should be vigilant for dispro-
portionally severe adverse effects. Vortioxetine, a
novel multimodal antidepressant with procholin-
ergic effects,9 may prove to be specifically effica-
cious in such presentations.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
HMW has received honoraria for attendance at
advisory board meetings and speaking at continu-
ing professional development meetings from
Lundbeck who market vortioxetine.
References
1. Wijkstra J, Lijmer J, Burger H, et al.
Pharmacological treatment for psychotic
depression. Cochrane Database Syst Rev 2015; 7:
CD004044.
2. Singh J, Kour K and Jayaram MB.
Acetylcholinesterase inhibitors for schizophrenia.
Cochrane Database Syst Rev 2012; 1: CD007967.
3. Manganelli F, Vitale C, Santangelo G, et al.
Functional involvement of central cholinergic
circuits and visual hallucinations in Parkinson’s
disease. Brain 2009; 132: 2350–2355.
4. Ukai K, Fujishiro H, Iritani S, et al. Long-
term efficacy of donepezil for relapse of visual

hallucinations in patients with dementia with
Lewy bodies. Psychogeriatrics. 16 December
2014. DOI: 10.1111/psyg.12089. [Epub ahead
of print]
5. Patel S, Attard A, Jacobsen P, et al.
Acetylcholinesterase inhibitors (AChEi’s)
for the treatment of visual hallucinations in
schizophrenia: a review of the literature. BMC
Psychiatry 2010; 10: 69.
6. Blom JD, Coebergh JA, Lauw R, et al. Musical
hallucinations treated with acetylcholinesterase
inhibitors. Front Psychiatry 2015; 6: 46.
journals.sagepub.com/home/tpp 61
C Smart, H McAllister-Williams et al.
7. Shekhar A, Potter WZ, Lightfoot J, et al. Selective
muscarinic receptor agonist xanomeline as a
novel treatment approach for schizophrenia. Am J
Psychiatry 2008; 165: 1033–1039.
8. Lu PH, Edland SD, Teng E, et al. Donepezil
delays progression to AD in MCI subjects with
depressive symptoms. Neurology 2009; 72:
2115–2121.
9. Sanchez C, Asin KE and Artigas F. Vortioxetine, Visit SAGE journals online
a novel antidepressant with multimodal activity: journals.sagepub.com/
home/tpp
review of preclinical and clinical data. Pharmacol
Ther 2015; 145: 43–57. SAGE journals