Pregabalin withdrawal symptoms I Case notes

Depression with psychosis following

pregabalin discontinuation
Aws Sadik BA, MBBChir, Matthew Jelley MBChB, FRCPsych, Rosalind Ward MBChB, MRCPsych
There has been controversy about
Table 1. Blood test results on admission (abnormalities highlighted in bold)
the efficacy of pregabalin for
some indications, as well as the Test Result Reference range
potential for misuse and adverse
effects. Here, the authors discuss White blood count 10.5 x109/L 4.0–11.0
a female who was admitted with Haemoglobin 124 g/L 115–165
symptoms of severe depression
Platelets 334 x10 /L9
150–400
and psychotic features with a
potential causation of Sodium 130 mmol/L 133–146
discontinuation of pregabalin that Potassium 4.9 mmol/L 3.5–5.5
had been used for several years.
due to chronic back pain. Creatinine (serum) 95 µmol/L 45–84

Urea 9.7 mmol/L 2.5–7.8

P regabalin is a widely prescribed

medication with indications includ-
ing neuropathic pain, generalised
Calcium 2.62 mmol/L 2.20–2.60

Adjusted calcium 2.59 mmol/L 2.20–2.60

anxiety disorder and as an adjuvant in
focal seizures. However, there has
been controversy about the efficacy of
pregabalin for some indications,1 as
well as the potential for misuse and
adverse effects.2 In the UK, pregabalin
and gabapentin were reclassified as
class C controlled substances from
April 2019 due to evidence of rising
fatalities linked to their use.
There is little published evidence
regarding the risks of pregabalin dis-
continuation. In our clinical practice
we have observed several cases of pro-
longed psychiatric symptoms follow-
ing the cessation of pregabalin.
Building the evidence base around
possible sequelae of pregabalin dis-
continuation, and management of
these, is important to the safe use of
this medication.
We believe that this is the first pub-
lished account of a case of depression
with psychotic features following pre-
gabalin discontinuation. It serves to
highlight depression with psychosis
as a possible consequence of pregab-
alin discontinuation and encourage
Phosphate 1.8 mmol/L
Albumin (serum) 47 g/L
Bilirubin 18 µmol/L
TSH 5.66 mIU/L
Free T3 27.3 pmol/L
CRP 1 mg/L
discussion around the extent to which
this psychiatric presentation can be
attributed to pregabalin.
Case presentation
A 74-year-old female presented to the
emergency department with slowed
thoughts and suicidality. She was
accompanied by her husband who
described 72 hours of unusual behav-
iour, including sitting in silence at the
end of the bed with a vacant expres-
sion for prolonged periods, picking
up dust from the carpet and a scream-
ing episode overnight.
He also described a five-month his-
tory of low mood, anxiety and suicidal
thoughts; six weeks of insomnia,
0.8–1.5
35–50
<22
0.30–5.00
12.0–22.0
<5
reduced appetite and weight loss; four
weeks of reduced concentration,
anhedonia, social withdrawal and
hopelessness, and three weeks of eat-
ing no proper meals at all through
lack of appetite.
Further collateral history from her
husband included a past medical his-
tory of hypothyroidism, migraine,
lumbar discectomy and chronic back
pain. He was not aware of any psychi-
atric history or allergies. Current med-
ications were levothyroxine 75mg
once daily, paracetamol 1g four times
a day and candesartan 2mg once daily.
He also reported that the patient had
titrated down pregabalin over several
months and stopped it one month

wchh.onlinelibrary.wiley.com Progress in Neurology and Psychiatry I Vol. 25 Iss. 1 2021 I 19


Case notes I Pregabalin withdrawal symptoms
prior. The patient had frequently
visited her general practitioner (GP)
over the prior five months, in order to
titrate down pregabalin and attempt
to manage the symptoms described in
the previous paragraph. Additionally,
she had attended the emergency
department one week before this pres-
entation, reporting chronic back pain,
and was discharged to the care of her
GP after no indications for urgent
investigation or admission were iden-
tified. A referral to the local Improv-
ing Access to Psychological Therapies
service was subsequently made by the
GP. A timeline and further details of
these visits are summarised in the dis-
cussion section of this report.
The patient was reported to be a
non-smoker and non-drinker, with no
family history of psychiatric condi-
tions. She lived with her husband and
premorbidly was fully independent
with activities of daily living, although
always had ‘a degree of anxiety’.
On mental state examination, the
patient appeared anxious with fidgety
hands, a taut facial expression and
tearfulness. Her verbal responses were
delayed, very slow and broken. Phrases
spoken included: ‘I can’t talk to any-
one now’; ‘I’m too far in my mind’,
and ‘I feel sorry for…’ with no further
explanation. She expressed suicidal
ideation, but no plans, and denied
hallucinations, however, she appeared
to be responding to unseen external
stimuli. She was orientated to time
and place, but showed poor concen-
tration. No positive findings were elic-
ited on physical examination,
including signs of infection, organo-
megaly or focal neurological deficit.
The patient was admitted under
the medical team for the investiga-
tions of behavioural and cognitive
changes. Input from the mental
health liaison team was also invited.
Investigations
Initial blood tests demonstrated
derangements in sodium, creatinine,
20 I Progress in Neurology and Psychiatry I Vol. 25 Iss. 1 2021
urea, phosphate, thyroid stimulating
hormone and free thyroxine levels
(Table 1).
Disorders such as thyroid autoim-
mune conditions, adrenal insuffi-
ciency, hyperparathyroidism and
myeloma were essentially ruled out by
subsequent blood tests to investigate
these derangements. Serum thyroid
antibodies, cortisol, parathyroid hor-
mone, immunoglobulins, free light
chains and protein electrophoresis
were all within reference ranges. Addi-
tionally, urine Bence-Jones protein,
sodium, potassium and osmolality
were also within reference ranges, rul-
ing out myeloma, renal salt loss and
syndrome of inappropriate antidiu-
retic hormone secretion (SIADH). A
chest X-ray showed no abnormality,
such as evidence of a malignancy or
pneumonia, that could cause hyper-
calcaemia or acute kidney injury,
respectively.
A CT head scan was performed on
admission and showed no acute
intracranial abnormalities. Subse-
quent MRI brain also did not find any
structural abnormalities.
Differential diagnosis
The patient presented with symptoms
of depression and evidence of halluci-
nations. The new onset of these symp-
toms warranted investigations for
organic causes, particularly given the
age at onset and severity of symptoms.
The list of possible organic causes of
depression and psychosis are exten-
sive and include neurodegenerative,
neurological, infectious, inflamma-
tory, metabolic, endocrine and onco-
logical causes, as well as adverse effects
of substances or their withdrawal.
Physical examination elicited no
symptoms suggestive of a particular
organic cause. Initial investigations
identified hyponatraemia, acute kid-
ney injury, hyperphosphataemia and
thyroid hormone derangements.
In a patient with known hypothy-
roidism, concurrently raised thyroid
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stimulating hormone and free T3
levels are characteristic of inconsistent
levothyroxine administration. This
aetiology can be confirmed by repeat-
ing the thyroid function tests after sev-
eral days of consistent medication
administration. Hyponatraemia, acute
kidney injury and hyperphosphatae-
mia each have a range of potential
underlying causes that can be elicited
through examination and further
investigations. In this case, further
investigations were unremarkable,
indicating that each of these was
explained by dehydration secondary
to reduced fluid intake.
Withdrawal from a range of sub-
stances may trigger psychotic symp-
toms. Alcohol withdrawal is an
important consideration; however, the
patient was reported not to drink alco-
hol and there were no other findings
characteristic of alcohol withdrawal.
Pregabalin cessation was raised by
family members as a possible cause for
this presentation. Pregabalin is not
widely considered a cause of severe
depression or psychosis, however, this
is considered further in the discussion
section of this report.
Treatment
Following baseline investigations, can-
desartan was stopped (due to acute
kidney injury) and intravenous fluids,
intravenous thiamine, oral laxatives
and nutritional supplements were
started. Following a review by the men-
tal health liaison team, olanzapine
5mg once daily was started for treat-
ment of psychotic depression. Mir-
tazapine 15mg once daily was added
two days later.
By the eighth day of the admission,
blood test derangements had normal-
ised with no improvement in mental
state. Further evidence of hallucina-
tions, suicidality and confusion was
seen and medications, food, fluids
and a nasogastric tube were being
refused. Thus, a decision was made to
apply for detention under the Mental
wchh.onlinelibrary.wiley.com

Health Act (MHA) 1983, of England
and Wales, and to start emergency
electroconvulsive therapy (ECT) for
life-threatening depression with psy-
chosis. The MHA assessment was com-
pleted the following day and the
patient was detained under Section 2
of the MHA 1983. During the MHA
assessment, a capacity assessment was
carried out; the patient was felt to be
able to understand, retain and com-
municate information around mental
health treatment, but unable to use or
weigh up this information due to her
low mood and hopelessness.
Outcome and follow-up
ECT was first administered on the
tenth day of admission under Section
62 of the MHA 1983, with an improve-
ment in behaviour, appetite and fluid
intake evident the next day. A second
opinion appointed doctor (SOAD)
report and form T6 were completed
after the second administration of
ECT, allowing up to 12 ECT treat-
ments in total. On the eighteenth day
of admission and after the third
administration of ECT, the patient was
well enough to be discharged from
hospital having undergone a period of
monitoring for refeeding syndrome
(a potentially fatal disturbance in fluid
and electrolytes that can occur during
the reintroduction of nutrition in
starved individuals.) It was agreed
that medication and ECT would be
continued on an outpatient basis.
Thirty days after the original
admission date and following five
administrations of ECT in total, it was
agreed to pause ECT treatment and
increase the dose of mirtazapine to
30mg once daily. Thirty-seven days
after the admission date, it was agreed
to stop ECT and continue olanzapine
5mg once daily and mirtazapine 30mg
once daily.
Outpatient follow-up continued,
with a full remission from the
depressive episode declared at three
months after admission. Olanzapine
wchh.onlinelibrary.wiley.com
Pregabalin withdrawal symptoms I Case
was gradually reduced and stopped at
seven months after admission. There
had been no relapse as of 11 months
post-admission and the patient’s regu-
larly prescribed medications at that
point were levothyroxine 75mg once
daily, mirtazapine 45mg once daily,
paracetamol 1g four times a day and
sumatriptan 50mg, when required
for migraine.
Discussion
Our primary point of interest in this
case is whether the episode of depres-
sion with psychosis was precipitated by
the discontinuation of pregabalin, as
an understanding of the aetiology of a
condition is the foundation to its pre-
vention. With this hypothesis in mind,
a review of the primary care records
was carried out, as well as further dis-
cussion with the patient.
Throughout the patient’s primary
care records there was no docu-
mented diagnosis of depression, anxi-
ety or psychosis, although trials of
mirtazapine and citalopram had pre-
viously occurred for unspecified indi-
cations. The patient had experienced
back pain for many years, with amitrip-
tyline and nortriptyline briefly trialled
in the past for this indication. These
were stopped due to adverse effects:
hallucinations and constipation,
respectively. Gabapentin was started
seven years prior to this admission,
used up to a dose of 600mg three
times a day, and stopped four years
prior to this admission due to a loss of
effectiveness. Gabapentin was
replaced by pregabalin, which was
titrated up to 300mg twice daily and
continued for over three years.
Five months prior to this admis-
sion, a plan to titrate down the daily
dose of pregabalin by 100mg/day
each week and then stop was agreed,
due to the patient’s concerns around
reports of pregabalin addiction. After
one week, the plan was abandoned
temporarily due to severe headaches
when the dose was reduced.
Progress in Neurology and Psychiatry I Vol. 25 Iss. 1 2021 I 21
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notes
Three and a half months prior to
this admission, a plan to titrate down
the daily dose of pregabalin by 50mg/
day each week and then stop was
agreed. As the dose of pregabalin was
reduced, a number of symptoms
emerged, including low mood, insom-
nia, nausea, poor appetite, dizziness
and back pain, with trials of duloxe-
tine, cyclizine and a buprenorphine
patch carried out in order to manage
some of these. Complete cessation of
pregabalin was achieved approxi-
mately 30 days before the admission,
however, the symptoms continued to
worsen during this time. A timeline
of medication changes and symp-
toms before admission is presented
in Table 2.
The patient reported that she felt
symptoms worsening with every
decrease in the pregabalin dose.
Additionally, she recalled two
previous occasions when she had
forgotten to take a dose of pregaba-
lin and felt ‘awful withdrawal symp-
toms’ for up to several days.
Pregabalin discontinuation symp-
toms are a recognised phenomenon.
The British National Formulary rec-
ommends that, if treatment cessation
is planned, pregabalin should be
tapered over at least one week.3 The
Electronic Medicines Compendium
reports that withdrawal symptoms
have been observed in some patients
in the past, with pain, insomnia, nau-
sea, anxiety, depression and convul-
sions included as mentioned events. It
is recommended that patients should
be informed of about this at the start
of treatment.4
Psychotic symptoms have been
reported in case reports as conse-
quences of pregabalin use5,6,7 and
cessation,8 as well as following the
initiation9 and cessation10,11 of the
closely related medication gabapen-
tin. Several substances that increase
GABA receptor activity are well
known to cause psychotic symptoms
on discontinuation, including alcohol

Case notes I Pregabalin withdrawal symptoms
and benzodiazepines. Although pre-
gabalin does not act directly at GABA
receptors, it is thought to increase syn-
aptic GABA concentrations and shares
other characteristics with substances
that do increase GABA activity, such as
anxiolysis and sedation. It has been
suggested that psychosis may be trig-
gered by an increase in dopaminergic,
serotonergic and noradrenergic activ-
ity when the GABAergic effect of pre-
gabalin is withdrawn.
We cannot confidently quantify
the role of pregabalin versus other fac-
tors in the development of severe
depression with psychosis in this case.
However, we strongly suspect with-
drawal of pregabalin as a counterfac-
tual cause12 (ie if the use and cessation
of pregabalin had not occurred,
severe depression with psychosis
would not have occurred). In any
event, this case raises the importance
of considering adverse effects when
Table 2. Pre-admission timeline of pregabalin taper and symptom onset
No. weeks Pregabalin dose
pre-admission (mg AM/mg PM)
24 300/300
23 200/300
16 300/300
13 250/200
12 200/200
9 150/100
7 50/50
6 50/0
5 50/0
4 0/0
3 0/0
2 0/0
1 0/0
0 0/0
22 I Progress in Neurology and Psychiatry I Vol. 25 Iss. 1 2021
decisions are being made to start pre-
gabalin. Furthermore, this case report
indicates that regular review may be
helpful in identifying and managing
the development of psychiatric symp-
toms during pregabalin cessation. In
this case, the general practitioner did
indeed keep frequent contact with the
patient and actively sought to manage
the emerging symptoms, highlighting
that it may not always be possible to
prevent the onset of psychopathology
despite our best efforts.
Learning points
• Pregabalin discontinuation can be
associated with distressing symp-
toms, although these are not well
characterised.
• Before starting treatment, it is impor-
tant to inform patients of the potential
adverse effects of pregabalin use,
including discontinuation symptoms.
• It is possible that severe depression
Comments
Agreed to reduce pregabalin by 100mg/week
Reduction caused severe headaches; return to 300/300
Agreed to reduce by 50mg/week
Increased pain; reduced appetite, mood and sleep.
Duloxetine started
Duloxetine caused sweating and nausea, so stopped
Feeling okay
Off food
Buprenorphine patch 5mg/24hrs started for pain
Dizziness, nausea, insomnia, tremor
Dizziness, nausea. Trial of cyclizine started
Nausea, weakness, retching. Cyclizine stopped.
Endoscopy requested
Buprenorphine patch stopped due to side-effects
Visited A&E due to pain. Not admitted
Visited A&E due to change in behaviour. Admitted
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and psychosis can be precipitated by
the discontinuation of pregabalin.
Declaration of interests
No conflicts of interest were declared.
Dr Sadik is Core Psychiatry Trainee at
Avon and Wiltshire Mental Health Part-
nership NHS Trust; Dr Jelley is Consultant
Liaison Psychiatrist for Older People at
Bath and North East Somerset Acute &
Royal United Hospital A&E Acute Liaison
Team, Avon and Wiltshire Mental Health
Partnership NHS; Dr Ward is Consultant
Old Age Psychiatrist and Training Pro-
gramme Director at Avon and Wiltshire
Mental Health Partnership NHS Trust
and Severn Postgraduate Medical Educa-
tion School of Psychiatry.
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