PHARMACOTHERAPY OF MOOD DISORDERS DR GIAN LIPPI CONSULTANT

PHARMACOTHERAPY OF MOOD DISORDERS DR GIAN LIPPI CONSULTANT PSYCHIATRIST UNIVERSITY OF PRETORIA & WESKOPPIES HOSPITAL FORENSIC UNIT

CONTENTS BASIC BACKGROUND PHYSIOLOGY BASICS OF PHARMACOTHERAPY OF MOOD DISORDERS ANTIDEPRESSANTS (ALL THE CLASSES) MOOD STABILIZERS (ALL THE CLASSES)

BASIC BACKGROUND PHYSIOLOGY PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

BASICS ANTIDEPRESSANTS ARE THE MAINSTAY OF TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD) - SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) SEROTONIN NORADRENALIN REUPTAKE INHIBITORS (SNRIs) SELECTIVE NORADRENALIN REUPTAKE INHIBITORS (NRIs) NORADRENALIN DOPAMINE REUPTAKE INHIBITORS (NDRIs) TRICYCLIC ANTIDEPRESSANTS (TADs) TETRACYCLIC ANTIDEPRESSANTS (TTADs) MONOAMINE OXIDASE INHIBITORS (MAOIs) REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE (RIMAs) NORADRENALIN & SPECIFIC SEROTONIN ANTAGONISTS (NASSAs) SEROTONIN ANTAGONIST / REUPTAKE INHIBITORS (SARIs) -MELATONIN ANTAGONISTS (MAs) MOOD STABILIZERS ARE THE MAINSTAY OF TREATMENT OF THE BIPOLAR DISORDERS - CLASSIC MOOD STABILIZER - ANTICONVULSANTS - ATYPICAL ANTIPSYCHOTICS

ANTIDEPRESSANTS

SSRIs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

SSRIs, GENERAL 1 ST LINE TREATMENT FOR MDD DRUGS & DOSAGES - FLUOXETINE 20 - 60 mg po mane PAROXETINE 20 - 50 mg po mane (AKA Prozac) CITALOPRAM 20 - 40 mg po mane ESCITALOPRAM 10 - 20 mg po mane SERTRALINE 50 - 200 mg po mane FLUVOXAMINE 50 - 150 mg po bd MOST COMMON SIDE-EFFECTS - SEXUAL DYSFUNCTION (DECREASED LIBIDO, ANORGASMIA, erectile dysfunction) NAUSEA, VOMITING, DIARRHOEA HEADACHE INSOMNIA

SNRIs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

SNRIs, GENERAL MOSTLY 2 ND LINE TREATMENT FOR MDD FOR TREATMENT AUGMENTATION, TREATMENT RESISTANT MDD & MDD WITH PROMINENT PAIN SYMPTOMS DRUGS & DOSAGES - VENLAFAXINE 75 - 300 mg po mane - DULOXETINE 60 - 120 mg po mane MOST COMMON SIDE-EFFECTS - GASTROINTESTINAL DISCOMFORT SEXUAL DYSFUNCTION SEDATION HYPOTENSION & TACHYCARDIA DRY MOUTH

NRIs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

NRIs, GENERAL MOSTLY INEFFECTIVE AS AN ANTIDEPRESSANT FOR AUGMENTATION TREATMENT IN MDD DRUGS & DOSAGES - REBOXETINE 4 - 5 mg po bd MOST COMMON SIDE-EFFECTS - URINARY HESITANCY CONSTIPATION HEADACHE NASAL CONGESTION PERSPIRATION DRY MOUTH DIZZINESS DECREASED LIBIDO INSOMNIA

NDRIs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

NDRIs, GENERAL MOSTLY 2 ND LINE ANTIDEPRESSANT FOR TREATMENT AUGMENTATION, MDD WITH PROMINENT HYPERSOMNIA & FATIGUE OR PATIENTS WITH SEXUAL DYSFUNCTION ON OTHER ANTIDEPRESSANTS DRUGS & DOSAGES - BUPROPION 150 - 300 mg po mane ( can also be used for smoking cessation) MOST COMMON SIDE-EFFECTS - HEADACHE - INSOMNIA - NAUSEA

TADs & TTADs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

TADs & TTADs, GENERAL MOSTLY 2 ND LINE ANTIDEPRESSANTS DUE TO LESS TOLERABLE SIDE -EFFECTS & RISK OF LETHAL ARRHYTHMIA WITH OVERDOSE EFFECTIVE ANTIDEPRESSANTS TADs - AMITRIPTYLINE 30 - 200 mg po nocte CLOMIPRAMINE 10 - 250 mg po nocte IMIPRAMINE 10 - 200 mg po nocte TRIMIPRAMINE 30 - 300 mg po nocte LOFEPRAMINE 140 - 210 mg po nocte (mostly used currently) TTADs - MAPROTILINE 75 - 200 mg po nocte (hardly used currently) MOST COMMON SIDE-EFFECTS - ANTICHOLINERGIC SIDE – EFFECTS, OFTEN SEVERE (CONSTIPATION, URINARY RETENTION, DRY MOUTH, BLURRED VISION) - SEDATION - ORTHOSTATIC HYPOTENSION - CARDIAC ARRHYTHMIAS WHICH CAN BE LETHAL IN OVERDOSES (MORE WITH TADs)

MAOIs & RIMAs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

MAOIs & RIMAs, GENERAL POWERFUL ANTIDEPRESSANTS NOT FOR 1 ST LINE TREATMENT MAOIs - TRANYLCIPROMINE 5 - 100 mg po bd RIMAs - MOCLOBEMIDE 75 - 300 mg po bd MOST COMMON SIDE-EFFECTS - ORTHOSTATIC HYPOTENSION INSOMNIA WEIGHT GAIN OEDEMA SEXUAL DYSFUNCTION TYRAMINE-INDUCED HYPERTENSIVE CRISIS - CAUSED BY INTAKE OF TYRAMINE – CONTAINING FOODS WHILST ON THE MEDICATION - SUCH FOODS MUST BE AVOIDED, THESE INCLUDE AGED CHEESES, FISH, BILTONG, MARMITE, SAUERKRAUT, BEER, CHIATI WINE, LIQUEUR

NASSAs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

NASSAs, GENERAL CAN BE USED AS 1 ST / 2 ND LINE TREATMENT, OR IN AUGMENTATION TREATMENT OF MDD OFTEN USED IN TREATMENT OF MDD WITH PROMINENT INSOMNIA DRUGS & DOSAGES - MIRTAZAPINE 15 - 45 mg po nocte MOST COMMON SIDE-EFFECTS - SEDATION WEIGHT GAIN INCREASED APPETITE DRY MOUTH

SARIs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER

SARIs, GENERAL NOT 1 ST LINE TREATMENT IN MDD MOSTLY INEFFECTIVE IN THE TREATMENT OF MDD OFTEN USED IN TREATMENT OF MDD WITH PROMINENT INSOMNIA DRUGS & DOSAGES - TRAZODONE 75 - 300 mg po bd MOST COMMON SIDE-EFFECTS - SEDATION ORTHOSTATIC HYPOTENSION DIZZINESS HEADACHE NAUSEA

MAs, MECHANISM OF ACTION PRESYNAPTIC SYNAPSE POSTSYNAPTIC MAO / COMT NEURON EFFECT RECEPTOR NEUROTRANSMITTER 22

MAs, GENERAL NOT 1 ST LINE TREATMENT IN MDD OFTEN USED IN TREATMENT OF MDD WITH PROMINENT INSOMNIA DRUGS & DOSAGES - AGOMELATINE 25 -50 mg po nocte MOST COMMON SIDE-EFFECTS - DIZZINESS - NAUSEA 23

MOOD STABILIZERS

INDICATIONS & CATEGORIZATION TREATMENT OF THE MAINTENANCE PHASE OF BIPOLAR DISORDERS TREATMENT OF MANIC EPISODES TREATMENT OF HYPOMANIC EPISODES TREATMENT OF DEPRESSIVE EPISODES TREATMENT OF MIXED EPISODES 3 GROUPS OF MOOD STABILIZERS - CLASSIC MOOD STABILIZER - ANTICONVULSANTS - ATYPICAL ANTIPSYCHOTICS

CLASSIC MOOD STABILIZER LITHIUM INDICATIONS - 1 ST LINE TREATMENT OPTION IN BIPOLAR DISORDERS (MAINTENACE PHASE) - MOST EFFECTIVE IN TREATING & PREVENTING MANIC EPISODES - CAN BE CONSIDERED FOR TREATMENT OF MIXED EPISODES & RAPID CYCLING, ST BUT NOT 1 LINE - QUESTIONABLE EFFICACY IN TREATMENT, NOT PREVENTION OF BIPOLAR DEPRESSION DOSAGE, THERAPEUTIC INDEX & MONITORING OF LITHIUM BLOOD LEVELS - DOSE IS ACCORDING TO TROUGH LEVEL OF LITHIUM IN THE BLOOD START AT LOW DOSE, INCREASE SLOWLY & ADJUST DOSE ACCORDING TO LITHIUM LEVEL SAFE STARTING DOSE IS 500 mg po mane LITHIUM HAS A VERY NARROW THERAPEUTIC INDEX: LITHIUM LEVEL OF 0, 5 – 0. 9 FOR THE MAINTENANCE PHASE LITHIUM LEVEL OF UP TO 1, 5 FOR THE TREATMENT OF A MANIC EPISODE (ACUTE) LEVELS BELOW THIS RANGE RESULTS IN TOTALLY INEFFECTIVE TREATMENT LEVELS ABOVE THIS RANGE CAN RESULT IN POTENTIALLY LETHAL LITHIUM TOXICITY LITHIUM LEVELS NEED TO BE CHECKED 4 DAYS AFTER STARTING TREATMENT OR CHANGING DOSE LITHIUM LEVELS NEED TO BE CHECKED 6 -MONTHLY WHEN A PATIENT IN THE MAINTENANCE PHASE HAS STABLE BLOOD LEVELS WITHIN THERAPEUTIC RANGE - LITHIUM BLOOD LEVELS ARE TROUGH LEVELS, SO WHEN BLOOD IS DRAWN TO TO CHECK THE LEVELS, IT MUST BE DRAWN JUST BEFORE THE NEXT DOSE

CLASSIC MOOD STABILIZER LITHIUM MOST COMMON SIDE-EFFECTS - NAUSEA, VOMITING, DIARRHOEA - WEIGHT GAIN & FLUID RETENTION - POSTURAL TREMOR - RENAL EFFECTS: POLYURIA WITH SECONDARY POLYDIPSIA HYPOKALAEMIA RARELY NONSPECIFIC INTERSTITIAL FIBROSIS WITH MORE THAN 10 YEARS OF LITHIUM USE - BENIGN, USUALLY REVERSIBLE THYROID EFFECTS: MOST COMMONLY HYPOTHYROIDISM HYPERTHYROIDISM GOITER & EXOPHTHALMUS - CARDIAC EFFECTS SECONDARY TO HYPOKALAEMIA: T-WAVE FLATTENING OR INVERSION ON ECG SINUS DYSRHYTHMIAS, HEART BLOCK, SYNCOPE EPISODES - TERATOGENESIS: CAN CAUSE EBSTEIN’S ANOMALY IN THE UNBORN FETUS OF A PREGNANT MOTHER ON LITHIUM TOXICITY - TREMOR, DYSARTHRIA, ATAXIA NAUSEA, VOMITING, DIARRHOEA CARDIOVASCULAR CHANGES & RENAL DYSFUNCTION MYOCLONUS & MUSCULAR FASCICULATIONS SEIZURES, IMPAIRED LEVEL OF CONSCIOUSNESS, COMA MEDICAL EMERGENCY, TREAT BY STOPPING LITHIUM & PUSHING INTRAVENOUS FLUIDS

CLASSIC MOOD STABILIZER LITHIUM BEFORE STARTING A PATIENT ON LITHIUM THE FOLLOWING SPECIAL INVESTIGATIONS NEED TO BE DONE TO CHECK IF HE/SHE IS A SUITABLE CANDIDATE FOR THE TREATMENT: - UKE (CHECK POTASSIUM & SIFT FOR KIDNEY DYSFUNCTION) - CREATININE CLEARANCE (LITHIUM IS EXCRETED EXCLUSIVELY BY THE KIDNEYS, KIDNEY FUNCTION NEEDS TO BE INTACT) - FBC (CHECK LEUCOCYTES TO GET A BASELINE VALUE, LITHIUM CAN CAUSE LEUCOCYTOSIS) - TSH (CHECK FOR HYPO/HYPERTHYROIDISM, LITHIUM CAN INTERFERE WITH THYROID FUNCTION) - ß-HCG IN FEMALES (LITHIUM IS TERATOGENIC) - ECG (CHECK FOR DYSRHYTHMIA /HEART BLOCK) MONITORING OF THE PATIENT ON LITHIUM - UKE (IN 1 ST MONTH AFTER STARTING LITHIUM, THEN 6 -MONTHLY IF NORMAL TO MONITOR POTASSIUM & LONG-TERM KIDNEY FUNCTION WHICH CAN DETERIORATE ON CHRONIC LITHIUM TREATMENT) - FBC (PERIODICALLY TO CHECK FOR LEUCOCYTOSIS) - TSH (IN 1 ST MONTH AFTER STARTING LITHIUM, THEN 6 -MONTHLY IF NORMAL TO CHECK FOR HYPO/HYPERTHYROIDISM) - ß-HCG IN FEMALES (PERIODICALLY TO CHECK FOR PREGNANCY) - ECG (IN 1 ST MONTH AFTER STARTING LITHIUM, THEN PERIODICALLY TO CHECK FOR T-WAVE FLATTENING OR INVERSION, DYSRHYTHMIA/HEART BLOCK) - LITHIUM LEVELS (4 DAYS AFTER STARTING LITHIUM/CHANGING DOSE, THEN 3 -6 MONTHLY TO CHECK FOR TOXICITY/SUB-THRESHOLD DOSING/NEED FOR DOSAGE ADJUSTMENT)

ANTICONVULSANTS VALPROATE INDICATIONS - 1 ST LINE TREATMENT OPTION IN BIPOLAR DISORDERS (MAINTENANCE PHASE) MOST EFFECTIVE IN TREATING & PREVENTING MANIC EPISODES TREATMENT OF CHOICE FOR MIXED EPISODES & RAPID CYCLING NOT EFFECTIVE IN TREATMENT & PREVENTION OF DEPRESSION ADVANTAGE OF BEING ABLE TO TITRATE DOSE UPWARDS RAPIDLY DOSAGE - 250 -1250 mg po bd MOST COMMON SIDE-EFFECTS - SEDATION WEIGHT GAIN THROMBOCYTOPAENIA HAIR LOSS AT HIGH DOSES TREMOR MONITORING OF THE PATIENT ON VALPROATE - LFT (BEFORE STARTING TREATMENT TO CHECK FOR IMPAIRED LIVER FUNCTION SINCE VALPROATE IS METABOLIZED BY THE LIVER, THEN 6 -MONTHLY TO CHECK FOR THE RARE SIDE-EFFECT OF POTENTIALLY FATAL HEPATOTOXICITY SEEN MOSTLY IN PAEDIATRIC PATIENTS)

ANTICONVULSANTS CARBAMAZEPINE INDICATIONS - FALLEN OUT OF FAVOUR, NO LONGER ROUTINELY USED, ONLY IN SPECIFIC CASES - SAME USE PROFILE AS VALPROATE BUT SEEMS TO BE LESS EFFECTIVE DOSAGE - STARTING DOSE 200 mg po bd, TITRATE UP SLOWLY BY 200 mg AT A TIME - MAINTENANCE DOSE 300 -600 mg po bd MOST COMMON SIDE-EFFECTS - RASH (EXFOLIATIVE DERMATITIS) HYPONATREMIA & SYNDROME OF INAPPROPRIATE ADH SECRETION (SIADH) GASTROINTESTINAL SIDE-EFFECTS HEPATITIS RARELY AGRANULOCYTOSIS/APLASTIC ANAEMIA (BONE MARROW SUPPRESSION) INTERFERES WITH THE METABOLISM OF OTHER DRUGS MONITORING OF THE PATIENT ON CARBAMAZEPINE - LFT (BEFORE STARTING TREATMENT TO CHECK FOR IMPAIRED LIVER FUNCTION SINCE CARBAMAZEPINE IS METABOLIZED BY THE LIVER, THEN PERIODICALLY TO CHECK FOR HEPATITIS) - UKE (BASELINE BEFORE STARTING TREATMENT THEN PERIODICALLY TO CHECK FOR HYPONATREMIA & SIADH) - FBC (BASELINE BEFORE STARTING TREATMENT THEN PERIODICALLY TO CHECK FOR BONE MARROW SUPPRESSION)

ANTICONVULSANTS LAMOTRIGINE INDICATIONS - 1 ST LINE TREATMENT OPTION FOR PATIENTS WITH PROMINENT BIPOLAR DEPRESSION EFFECTIVE IN TREATING DEPRESSIVE EPISODES TREATMENT OF CHOICE FOR PREVENTING DEPRESSIVE EPISODES EFFECTIVE IN PREVENTING MANIC EPISODES NOT EFFECTIVE IN TREATMENT OF MANIC EPISODES POSSIBLE / QUESTIONABLE EFFICACY IN TREATMENT OF MIXED EPISODES & RAPID CYCLING DOSAGE - STARTING DOSE 25 mg po nocte, TITRATE UP SLOWLY BY 25 mg EVERY 2 WEEKS TO DECREASE THE RISK OF STEVENS-JOHNSON SYNDROME - MAINTENANCE DOSE 100 -200 mg po nocte MOST COMMON SIDE-EFFECTS - DIZZINESS & ATAXIA BLURRED VISION & DIPLOPIA HEADACHE SEDATION NAUSEA & VOMITING STEVENS-JOHNSON SYNDROME (IF A RASH DEVELOPS, STOP LAMOTRIGINE IMMEDIATELY)

ATYPICAL ANTIPSYCHOTICS INDICATIONS - EFFECTIVE IN TREATMENT OF MANIC EPISODES EFFECTIVE IN PREVENTING MANIC EPISODES EFFECTIVE IN TREATING DEPRESSIVE EPISODES NOT EFFECTIVE IN PREVENTING DEPRESSIVE EPISODES CAN BE CONSIDERED FOR TREATMENT OF MIXED EPISODES & RAPID CYCLING, BUT NOT 1 ST LINE DRUGS & DOSAGE - OLANZAPINE 10 -20 mg po nocte - QUETIAPINE 300 -800 mg po nocte - ARIPIPRAZOLE 10 -30 mg po nocte MOST COMMON SIDE-EFFECTS - METABOLIC SYNDROME (MS) – WEIGHT GAIN WITH CENTRAL OBESITY + HYPERTENSION + HYPERCHOLESTEROLAEMIA + HYPERGLYCAEMIA - OLANZAPINE – SEVERE MS, SEDATION, DIZZINESS, DRY MOUTH, CONSTIPATION, DYSPEPSIA, AKATHISIA - QUETIAPINE – MS, SEVERE SEDATION, DIZZINESS, POSTURAL HYPOTENSION - ARIPIPRAZOLE – HEADACHE, SEDATION, AKATHISIA, AGITATION, ANXIETY, DYSPEPSIA, NAUSEA NOT MS MONITORING OF THE PATIENT ON ATYPICAL ANTIPSYCHOTICS - BASELINE FASTING GLUCOSE & LIPOGRAM, BLOOD PRESSURE, WAIST CIRCUMFERENCE, WEIGHT MEASUREMENT - FASTING GLUCOSE & LIPOGRAM, BLOOD PRESSURE, WAIST CIRCUMFERENCE, WEIGHT MEASUREMENT 1 MONTH AFTER STARTING TREAMENT, THEN 6 -MONTHLY - MORE REGULAR MONITORING FOR OLANZAPINE OR IF THERE ARE SIGNS OF MS

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