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Pharmacology of Depression Katerina Loupasaki al2120@ic.ac.ukOBJECTIVES: • Describe how depression presents • Use diagnostic tools for depression • Describe the pathophysiology of depression • Explain the mechanism of drugs used to treat depression • Recognise the side effects and contraindications of these drugs Plan for today Pathophysiology Prescribing What is depression? MedicationsCurtis Nash • 47, male • Low mood • “Can’t seem to enjoy anything anymore” → Anhedonia • Low self-esteem • Sleep difficulties • Inability to think clearly • Duration of symptoms: 1 month+Diagnosis of Depression Q1: How many symptoms must be present and for how long? A. At least 6 symptoms gradually presenting over 2 weeks B. At least 4 symptoms during the same month C. At least 5 symptoms during the same 2 weeks D. At least 6 symptoms during the same month E. At least 4 symptoms presenting over 3 or more weeksDiagnosis of Depression Q1: How many symptoms must be present and for how long? A. At least 6 symptoms gradually presenting over 2 weeks B. At least 4 symptoms during the same month C. At least 5 symptoms during the same 2 weeks D. At least 6 symptoms during the same month E. At least 4 symptoms presenting over 3 or more weeks For summative Diagnosis of Depression • 5 or more symptoms during the same 2-week period • At least one of the symptoms must be either (1) low mood or (2) anhedonia • Other symptoms: • Weight loss or weight gain, or decrease or increase in appetite • Insomnia or hypersomnia • Fatigue or loss of energy • Feelings of worthlessness or excessive guilt • Suicidal ideation • Indecisiveness, inability to think or concentrate Diagnosis of Depression • Patient Health Questionnaire 9 (PHQ-9): used to screen for depression • Patient’s score: 14 • Patient’s problem: Moderate depressionManagement of Depression Therapeutic objectives: Management: 1. Improve mood 1. Counseling, CBT 2. Help with sleep difficulties 2. Self-help 3. Improve his self-esteem 3. Medications 4. Improve his ability to think clearly 5. Help with everyday life Planfortoday Pathophysiology Prescribing What is depression? MedicationsPathophysiology of Depression Note: 5-HTP = derived from tryptophan 5-HT = Serotonin SERT= 5-HTTPathophysiology of Depression For summative Monoamine Hypothesis CNSunderpin the pathophysiology of depressionrepinephrineand/or dopamine in the Planfortoday Pathophysiology Prescribing What is depression? MedicationsMedications for Depression SSRIs Venlafaxine MirtazapineSelective Serotonin Reuptake Inhibitors: Examples: sertraline, citalopram, fluoxetine Target:serotonin transporter Location: pre-synaptic neuron Effect: increase serotonin availability in thesynapse SSRIs: Side effects GI disturbance – nausea, diarrhoea Sexual dysfunction Anxiety Insomnia • Act on other • Increase in • SSRI effects on • Activation of serotonin serotonin = serotonin 2C serotonergic 5- receptors too interference with receptors = HT2 receptors and • Stimulation of testosterone and increased anxiety increased serotonin dopamine and fear noradrenergic and receptors 3 and 4 dopaminergic = increased GI neurotransmission motilitySSRIs: Pharmacokinetics o Reduction in depressionratings plateausafter a certain dose o Numberof dropouts increases with increasing doseSSRIs: Pharmacokinetics o Reduction in depressionratings plateausafter a certain dose o Numberof dropouts increases with increasing doseV enlafaxine: Mechanism of Action o Venlafaxine: SNRI – serotoninand noradrenaline reuptakeinhibitor o Target:serotonin transporter, noradrenaline transporter o Location: pre- synaptic neuron V enlafaxine: Side effects GI disturbance – nausea, diarrhoea Sexual dysfunction Anxiety Insomnia • Act on other • Increase in • SSRI effects on • Activation of serotonin serotonin = serotonin 2C serotonergic 5- receptors too interference with receptors = HT2 receptors and • Stimulation of + HYPERTENSIONtosterone and increased anxiety increased serotonin dopamine and fear noradrenergic and receptors 3 and 4 dopaminergic = increased GI neurotransmission motilityMirtazapine: Mechanism of Action ▪ Antagonistat alpha- 2-adrenergic receptors= increased release of serotonin and noradrenaline ▪ Antagonistat central 5HT2 receptors= leaves 5HT1 receptorsunopposed = antidepressant effectMirtazapine: Mechanism of Action WHY? Mirtazapinedrugtargets • Sedation: H1 Highestaffinity Histamine(H1)receptor Sedation receptoractions Alpha-2receptor Anti-depressanteffect are mostly  excitatory Lowestaffinity 5HT2receptor Anti-depressanteffect • Anti-depressant 5HT3receptor Anti-emetic effect effect: alpha-2 receptorsinhibit the release of norepinephrine Mirtazapine: Mechanism of Action Efficacy: ability of a Affinity: Determines drug molecule to strength of binding of Specificity: ability to produce an effect the drug to the bind to the desired once bound to a receptor receptor receptorMirtazapine: Pharmacokinetics Mirtazapinedrugtargets Highestaffinity Histamine(H1)receptor Affinity: high for Sedation H1, lower for 5HT2 Alpha-2receptor Anti-depressanteffect  Specificity: low Lowestaffinity 5HT2receptor Anti-depressanteffect 5HT3receptor Anti-emetic effect Efficacy: antagonist so no efficacyMirtazapine: Side effects Mirtazapinedrugtargets ▪ Weight gain Highestaffinity Histamine(H1)receptor Sedation ▪ Low probability  Alpha-2receptor Anti-depressanteffect of sexual 5HT2receptor Anti-depressanteffect dysfunction Lowestaffinity 5HT3receptor Anti-emetic effect ▪ May exacerbate REM sleep behaviour disorder Planfortoday Pathophysiology Prescribing What is depression? MedicationsPrescribing Switching medications ContraindicationsSwitching medications • Washout required before starting a new drug • Must be gradually decreased on discontinuation • Otherwise: • Serotonin syndrome • Interactions • Withdrawal • Relapse Extra Info Serotonin Syndrome • Cause:too muchserotonin in theCNS • Culprits:overdose or therapeutic dose of serotonergic drugs • alteredmentalstatusneuromuscular excitation, autonomic effects,and • Signs:hyper-reflexia, clonus, hypertonia • Othersymptoms:anxiety,tachycardia,tremors, shivering, sweatingECG Practice!ECG Practice! QTc is prolonged if > 440ms in men or > 460ms in womenDrug InteractionsSUMMARY: Diagnosis Pathophysiology • DSM-5 Criteria • Serotonin production, release and reuptake system in the synapse • PHQ-9 for screening in primary • Targets for medication care Medications Interactions – Side effects • SSRIs • QT prolongation • Venlafaxine • Gradual dose decrease on • Mirtazapine discontinuationMentimeter Questions QR code Question 1 Feedback Which of the following effects of mirtazapine would occur Correct answer: C first with a low startingdose? Mirtazapine has a higher affinity for H1 receptorsthan for alpha-2, 5HT2 and A. Anti-depressanteffect 5HT3 receptors. B. Anti-emeticeffect C. Sedative effect At a low dose,mirtazapine will bind H1 receptorsmore strongly and therefore inducesedation. Question 2 Feedback Mariah, a 61-year-old woman presentstoGP with low Given thepatient’s age and symptoms, mood,weightgain, joint pains the listof potentialdiagnoses includes and difficulty sleeping. Which depressionas well as other conditions would be mostappropriate suchas perimenopause/menopause, action? hypothyroidism and osteoarthritis. Therefore,moreinvestigations are needed beforeany medicationcan be prescribed. Question 3 Feedback Lewis is a 55-year-old man who struggles with low mood Venlafaxine: cancausehypertension at and anhedonia. The GP diagnoses moderately severe higher doses so needto be carefulin depression.Lewis is also patients with uncontrolled struggling tocontrolhis blood hypertension pressureand has not been takinghis tablets regularly. Mirtazapine: considerweight gain side Which of the following effectin the contextof his hypertension medicationswould be more appropriate to prescribe? Citalopram: can causeserotonin syndrome and thereforehypertension, butthis is a rare complication. Question 4 Feedback Kara is a 46-year-old woman who presentswithanhedonia, Venlafaxine: cancausehypertension at sleeping difficulties,appetite changes and low mood.The GP higher doses – need to evaluatepatient diagnoses moderate depression and is consideringprescribing Mirtazapine: considerweight gain side an anti-depressant.Two effectin the contextof pre-diabetes monthsago, Kara saw theGP again for a checkup and was Sertraline: cancausesleeping informed shehas pre-diabetes. Which of the following difficulties medicationswould be more appropriate to prescribe? Question 5 Feedback A patientpresentstohospital after fainting on his way to Correct answer: Citalopram and work.An ECGis performed erythromycin whichshows a prolonged QT interval. Both canprolong the QTinterval and shouldnot be prescribedtogether. Which medicationcombination is the mostlikely causeof this finding?THANK YOU! Please fill in the Feedback form! QR code Name: Katerina Loupasaki Email: al2120@ic.ac.uk