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

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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