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 4
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 Low risk antipsychotics High risk antipsychotics
Aripiprazole Amisulpride Quetiapine Risperidone Lurasidone Paliperidone Clozapine Sulpiride Asenapine “Typical” / first generation antipsychotics Olanzapine? Causes of elevated prolactin 6
Physiological causes: Pharmacological causes Pathological causes • Pregnancy • Lactation • Antipsychotics • Prolactinoma • Stress (PRL levels of up to about 700 • Antidepressants* • Other pituitary or hypothalamic mU/L in men and 900 mU/L in • Opiates tumours or lesions women) • Peripheral dopamine receptor blockers • Hypothyroidism • Circadian variation (levels are e.g. metoclopramide, domperidone • Polycystic ovary syndrome highest in morning) • Antihypertensives e.g. calcium channel • Severe renal or liver disease • Macroprolactin (large molecular blockers, methyldopa aggregates lacking biological • H2 antagonists e.g. cimetidine activity but leading to falsely • Proton pump inhibitors e.g. omeprazole elevated PRL result. Screening for • Oestrogens macroprolactin is routinely conducted by the lab if PRL is found to be raised. )
* 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 8
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 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 medication
Therapeutic group Examples Opioids Pethidine, tramadol, methadone, fentanyl, dextromethorphan, pentazocine, oxycodone, tapentadol Parkinson’s disease Selegiline (MAO-B inhibitor), rasagiline (MAO-B inhibitor), levodopa, treatment 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 leaflets https://www.choiceandmedication.org/oxfordhealth/ Any questions