Adverse effects of psychotropic medication RACHEL BROWN CLINICAL LEAD PHARMACIST – CAMHS, MEDICINES ADVICE AND CLINICAL EFFECTIVENESS OXFORD HEALTH NHS FOUNDATION TRUST
Adverse effects of
psychotropic medication
RACHEL BROWN
CLINICAL LEAD PHARMACIST – CAMHS, MEDICINES ADVICE AND CLINICAL
EFFECTIVENESS
OXFORD HEALTH NHS FOUNDATION TRUST
Antipsychotic-induced hyperprolactinaemia
Serotonin Syndrome
Antipsychotic-induced
hyperprolactinaemia
Hyperprolactinaemia with APs
Dopamine inhibits prolactin release via D2 stimulation; serotonin promotes prolactin release via 5HT2A stimulation
All antipsychotics are D2 antagonists → block the effect of DA → prolactin levels rise
In the case of (most) second generation (atypical) there is simultaneous inhibition of 5HT2A receptors so serotonin can no longer stimulate prolactin release – theoretically cancel effects out
4
Low risk antipsychotics
Aripiprazole
Quetiapine
Lurasidone
Clozapine
Asenapine
High risk antipsychotics
Amisulpride
Risperidone
Paliperidone
Sulpiride
“Typical” / first generation
antipsychotics
Olanzapine?
Causes of elevated prolactin6
Physiological causes: • Pregnancy• Lactation• Stress (PRL levels of up to about 700
mU/L in men and 900 mU/L in women)
• Circadian variation (levels are highest in morning)
• Macroprolactin (large molecular aggregates lacking biological activity but leading to falsely elevated PRL result. Screening for macroprolactin is routinely conducted by the lab if PRL is found
to be raised. )
Pharmacological causes
• Antipsychotics • Antidepressants*• Opiates • Peripheral dopamine receptor blockers
e.g. metoclopramide, domperidone • Antihypertensives e.g. calcium channel
blockers, methyldopa • H2 antagonists e.g. cimetidine • Proton pump inhibitors e.g. omeprazole• Oestrogens
Pathological causes
• Prolactinoma • Other pituitary or hypothalamic
tumours or lesions • Hypothyroidism • Polycystic ovary syndrome • Severe renal or liver disease
* serotonin can also increase prolactin due to stimulation of 5HT2a receptors – therefore some
SSRIs may also raise prolactin, though this is rare.
Hyperprolactinaemia with APs
Often asymptomatic.
Can present acutely with gynaecomastia,
galactorrhoea, sexual dysfunction*
Long term risks are due to secondary
hypogonadism
reduction in Bone Mineral Density → osteoporosis
Guidelines
Consult your local trust’s AP induced hyperprolactinaemia guideline
(Oxford Health: http://www.oxfordhealthformulary.nhs.uk)
Guideline applies to all females <50 and males <65 years old
At baseline:
Prolactin measurement only for prolactin-raising APs – prior to antipsychotic use
Menstrual Hx women / sexual function men + women
After 3 months on STABLE dose:
Enquire about symptoms (acute plus indications of hypogonadism)
Measure prolactin ONLY if symptomatic
Guideline also covers scenario for patients already taking an AP who have never had their prolactin level checked
8
Guidelines
Prolactin normal – continue and no need to repeat unless AP dose increases
Prolactin raised – follow algorithm on page 2
Action depends on various factors including:
Age
Stress as a possible cause
Symptoms
Prolactin level (<3000 / >3000)
Feasibility of withholding antipsychotic for a few days
Whether or not a baseline was taken
http://www.oxfordhealthformulary.nhs.uk/docs/A
ntipsychotic%20induced%20hyperprolactinaemia
%20FINAL%20July%202015%20minor%20amend%20
to%20footer%20Jan%202016.pdf?UNLID=20118966
2201789114959
Action for symptomatic AP-induced hyperprolactinaemia
Dose reduction/switch?
Adjunctive aripiprazole?
Check prolactin monthly until normal
Consider if further investigations / referral are needed
Endocrinology
Bone health pathways
Address other risk factors for osteoporosis
Consider if contraceptive advice is needed (normalization of prolactin – return of fertility)
Avoid dopaminergic drugs to treat raised prolactin if at all possible.
Serotonin syndrome
Serotonin syndrome
Predictable effect of drug induced excess serotonin agonism
= form of poisoning rather than an idiosyncratic reaction
Hyperstimulation of the brain stem and spinal cord 5HT1A and 5HT2 receptors
Degree of elevation determines severity
Dose and potency for 5HT agonism influence toxicity
Triad of neuroexcitatory features
Altered mental status (agitation, excitement, confusion)
Neuromuscular hyperactivity (tremor, clonus, myoclonus, hyperreflexia)
Autonomic hyperactivity (diaphoresis, fever, mydriasis, tachycardia, tachypnoea
Mechanisms include
increase in serotonin synthesis
inhibition of serotonin metabolism
increase in serotonin release
inhibition of serotonin uptake
activation of serotonergic receptors
Spectrum of severity
Progression from side effects to life-threatening toxicity
Mild – insomnia, anxiety, nausea, diarrhoea, hypertension,
tachycardia, hyper-reflexia
Moderate – agitation, myoclonus, tremor, mydriasis, flushing,
diaphoresis, low fever (<38.5)
Severe – severe hyperthermia, confusion, rigidity, respiratory failure, coma, death
Marked fever (>38degreees) and rigidity = life threatening toxicity
Incidence and risk
Precise incidence unknown - incidence increasing due to:
Wide spread use of serotonergic medication
Better understanding / awareness of syndrome
Can be difficult to distinguish from other conditions e.g.
NMS
Anticholinergic toxicity
Malignant hyperthermia
Hunter serotonin toxicity criteria
In the presence of a serotonergic agent plus one
of the following:
Spontaneous clonus
Inducible or ocular clonus AND agitation or diaphoresis
Tremor AND hyperreflexia
Hypertonia AND hyperpyrexia (temperature exceeding
38ºC) AND ocular or inducible clonus
Main causes
Overdose of serotonergic drug e.g.
Moderate toxicity in 15% of patients who took SSRI overdose
Drug interactions – pharmacodynamic e.g.
Combination of two antidepressants (deliberate or a switch) e.g. MAOI + SSRI (severe); fluoxetine to SSRI/SNRI switch; antidepressant combined with other serotonergic medication e.g. tramadol + SSRI (mild – moderate)
Drug interactions – pharmacokinetic
Inhibiting the metabolism of a serotonergic medication with another drug (e.g. fluoxetine inhibits TCA metabolism by CYP2D6 inhibition)
Individual susceptibility
Serotonergic antidepressants
Therapeutic group Examples
SSRI antidepressants Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline
SNRI antidepressants Venlafaxine, duloxetine
MAOI antidepressants Tranylcypromine, phenelzine, moclobemide (reversible MAO-A
inhibitor), isocarboxazid
Tricyclic antidepressants Clomipramine, imipramine, amitriptyline, doxepin, nortriptyline,
trimipramine
Miscellaneous Lithium, trazodone, L-tryptophan, mirtazapine, vortioxetine,
bupropion
Other serotonergic medicationTherapeutic group Examples
Opioids Pethidine, tramadol, methadone, fentanyl, dextromethorphan,
pentazocine, oxycodone, tapentadol
Parkinson’s disease
treatment
Selegiline (MAO-B inhibitor), rasagiline (MAO-B inhibitor), levodopa,
amantadine, safinamide
Antibacterials Linezolid, tedizolid (reversible MAOI activity)
Anti-cancer drugs Procarbazine
Anticonvulsants Carbamazepine, valproate
Antiemetics Metoclopramide, ondansetron, granisetron
Antihistamines Chlorphenamine, diphenhydramine
Antimigraine drugs Triptans e.g. frovatriptan, almotriptan, eletriptan, naratriptan,
rizatriptan, sumatriptan, zolmitriptan. Dihydroergotamine.
Anti-smoking aids Bupropion
Anxiolytics Buspirone
Diagnostic dye Methylthioninium chloride (methylene blue)- has MAOI activity
Herbal products
Commonly asked medicines
advice question example: Can a triptan be used in someone already prescribed an SSRI?
Case reports of serotonin syndrome→ 2006 FDA review/ alert → mandated change to product licence wording (SPCs)
Interaction – pharmacokinetic and pharmacodynamic
Pharmacodynamic?
Triptans are agonists at 5HT1B/1D/1F receptors – only weak affinity for 5HT1A and no activity at 5HT2 → should not really be associated with SS
CYP2D6 inhibitors: (citalopram, escitalopram, fluoxetine, paroxetine, sertraline, fluvoxamine*, venlafaxine and duloxetine)
*also inhibits CYP1A2, 2C9, 2C19 and 3A4
Independent review of FDA cases – none met Hunter criteria for SS
Author conclusion: prohibiting use of triptans with SSRIs/SNRIs is not warranted
Calls made to review FDA advice
Triptans….the evidence against a
risk:
Prospective study (n= 12,339) s/c sumatriptan for 1 year
14.5% also took an SSRI – no reports of problems
US national survey data – estimated that 1.3million patients use the combination
UK GP database initial analysis of combined use of SRI+triptan (covering >5million patient years) – insufficient indication of association to warrant more detailed analysis
Retrospective population based analysis of a 14 year period - n=19,017 co-prescribed – 17 cases reported SS, but detailed medical review confirmed only 2
Triptans – what to do…? Choose lower lipophilicity (frovatriptan, sumatriptan)?
Less likely to cross BBB and interact - theoretical
No specific supporting evidence
Avoid long half life triptan?
In case of a problem – short half life = faster resolution
Frovatriptan 26 hours vs sumatriptan 2 hours
Theoretical…
Follow or ignore product licence??
Some triptan SPCs specifically mention the interaction with fluvoxamine
All SSRI, SNRI, mirtazapine SPCs highlight potential interaction
Only citalopram contraindicates use (but no evidence of this carrying a greater risk…)
Triptans – what to do…?
Probably all that is necessary:
highlight to the patient that the manufacturer’s PIL will mention this in
the warnings but evidence does not support the risk
advise to be vigilant for signs of SS
give SS PIL
May want to:
Use lower lipid soluble, short half life triptan (suma-, riza-, zolma-)
Avoid fluvoxamine with frovatriptan and zolmitriptan
Not use citalopram with any triptan
Other useful links and information www.sps.nhs.uk
What is serotonin syndrome and which medicines cause it?
(https://www.sps.nhs.uk/articles/what-is-serotonin-syndrome-and-which-medicines-cause-it-2/)
Triptans and SSRI or SNRI antidepressants – is there an interaction?
(https://www.sps.nhs.uk/articles/triptans-and-ssri-or-snri-antidepressants-is-there-an-interaction/)
What is the risk of developing serotonin syndrome following concomitant use of tramadol with an
SSRI? (https://www.sps.nhs.uk/articles/what-is-the-risk-of-developing-serotonin-syndrome-following-
concomitant-use-of-tramadol-with-selective-serotonin-reuptake-inhibitors-ssris/)
What is the risk of interaction between opioids and MAOIs? (https://www.sps.nhs.uk/articles/what-
is-the-risk-of-interaction-between-opioids-and-monoamine-oxidase-inhibitors-maois/)
How do you switch between SSRIs, TCAs and related antidepressants? (under review)
How do you switch between MAOIs and SSRIs, TCAs, or related antidepressants?
(https://www.sps.nhs.uk/articles/how-do-you-switch-between-monoamine-oxidase-inhibitors-and-
ssri-tricyclic-or-related-antidepressants/)
Maudsley Prescribing Guidelines in
Psychiatry (or other similar tables)
Other useful links
and information
Serotonin syndrome Patient
Information Leaflet
via Choice and Medication
link from Oxford Health’s
formulary homepage
(www.oxfordhealthformulary.
nhs.uk)
https://www.choiceandmedi
cation.org/oxfordhealth/gen
erate/handyfactsheetseroto
ninsyndrome.pdf
Patient information – “Choice and Medication”
Medicine leaflets
Translations
Picture leaflets for LD/ young people
Comparison charts
Handy fact sheets eg serotonin syndrome, EPS, NMS, hypersalivation
Mental health condition information
How medicines work booklet
Medicines in pregnancy leafletshttps://www.choiceandmedication.org/oxfordhealth/
Any questions