Pharmacotherapy in Mental Illness – Overview and Issues

Drugs for Med Students Presented by Eric Campbell, Jen

Chen & Esmond Wong

Depression Biogenic Amine Hypothesis:

Reserpine (used to treat hypertension)

–   Binds to storage vesicles in neurons (containing dopamine, serotonin, norepinephrine – “feel good neurotransmitters”

–   Decreases release –   Results in depressive symptoms

Antidepressants

•   Antidepressants work to increase biogenic amines in the synapse

•   This usually occurs by preventing reuptake into the presynaptic neuron

Tricyclic Antidepressant (TCAs)

Example: amitriptyline (Elavil)

•   Block various receptors in the brain resulting in increased serotonin and norepinephrine (good!)

•   Block other receptor systems as well –   Anticholinergic, neurologic, cardiovascular –   Results in extensive side effect profile

TCAs

Benefits / place in therapy •   Have been around a long time (1960’s) •   Major depression, depression of another mental illness,

bipolar depression, OCD, neuropathic pain •   Not used often for depression anymore – usually as a

sleep aid or for neuropathic pain

Cautions •   Patients with cardiac problems •   Can cause orthostatic hypotension, tachycardia,

conduction abnormalities •   suicidal patients (very toxic in overdose)

TCAs •   Taper gradually to avoid cholinergic rebound:

dizziness, nausea, diarrhea, insomnia, restlessness

•   many side effects: sedation, dry mouth, constipation, orthostatic hypotension, tachycardia, weight gain, sexual dysfunction

•   Usually dosed at bedtime to avoid adverse effects

•   Interactions –   Alcohol – increases TCA levels –   Anticonvulsants – increase/decrease TCA –   AD’s – sometimes combined for treatment resistant,

monitor for serotonin syndrome

List of Tricyclic Antidepressants

•   Amitriptyline-Elavil •   Clomipramine-Anafranil •   Desipramine-Norpramin •   Doxepin-Sinequan •   Imipramine-Tofranil •   Nortriptyline-Aventyl •   Trimipramine-Surmontil •   Maprotiline-Ludomil

Selective Serotonin Reuptake Inhibitors (SSRI)

Example: fluoxetine (Prozac)

•   inhibit serotonin reuptake by presynaptic neurons

•   Specific: no affect on NE or dopamine

SSRIs

Benefits/ Place in therapy •   Many indications including Major Depression,

bipolar depression, bulimia nervosa, OCD, panic d/o, social anxiety d/o

•   Possibly effective in smoking cessation, drug/etoh withdrawal, and neuropathic pain

•   SE profile more tolerable than older ADs •   Most popular class of antidepressants •   lower risk of dose related toxicity •   Benefit seen in 7-28 days

SSRIs Cautions •   serotonin syndrome: nausea, fever, diarrhea, chills, palpitations,

agitation, myoclonus, hyperreflexia •   activation or sedation, headache, nausea, & sexual side effects,

weight gain •   Taper slowly to avoid withdrawal symptoms •   Suicidal ideation

Interactions •   affect the metabolism of many other drugs – may need to adjust

dose •   Anticonvulsants – increase/decrease TCA levels •   combined with other antidepressants for additive effect in treatment

resistant patients •   Other serotonergic agents ex. anti emetics, migraine medications

List of SSRIs

•   Fluoxetine-Prozac •   Fluvoxamine-Luvox •   Paroxetine-Paxil •   Sertaline-Zoloft •   Citalopram-Celexa •   Escitalopram-Cipralex

Norepinephrine Dopamine Reuptake Inhibitor (NDRI)

Example: buproprion (Wellbutrin)

•   inhibit reuptake of NE (& dopamine to a lesser extent) into presynaptic neurons

•   No effect on serotonin

NDRIs

Benefits / Place in therapy: •   Major depression, bipolar depression,

neuropathic pain, ADHD •   Possibly lower switch rate c/t other AD’s

–   good choice for Bipolar Affective Disorder

•   Increase energy – good for retarded depression •   Can be used to treat SSRI induced sexual

dysfunction (no effect on serotonin) •   Smoking cessation (Zyban)

NDRIs Cautions •   Seizure disorder or conditions predisposing to seizures (alcohol,

BZD withdrawal, bulemia / anorexia) •   Insomnia (give 2nd dose in afternoon), exacerbation of psychosis,

palpitations, increased blood pressure, over stimulation, anxiety

Interactions •   Anticonvulsants can increase or decrease metabolism •   Decreased seizure threshold with quinolones, TCAs, thophylline,

stimulants •   Combined with TCA or SSRI in treatment resistance or help with AD

induced sexual dysfunction •   Amantadine / levodopa: increased dopamine – excitement,

restlessness, tremor

Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRI)

Example: venlafaxine (Effexor)

•   inhibits serotonin at low doses, NE at moderate, dopamine at high doses

•   place in therapy: Major depression, GAD, bipolar depression, neuropathic pain

•   benefit seen in 7-28 days

SNRIs

Cautions

•   hypertension –   increases BP, tachycardia

•   taper slowly to avoid withdrawal effects •   Tends to be stimulating at lower doses, sedating

at higher doses •   sexual dysfunction

Interactions •   Other AD’s: caution serotonin syndrome

List of SNRIs

•   Effexor-Venlafaxine •   Duloxetine-Cymbalta

Noradrenergic / Specific Serotonergic Antidepressant (NaSSA)

Example: mirtazapine (Remeron)

•   block pre-synaptic alpha-2 adrenergic and serotonin receptors

•   Cause increase in serotonin release without causing sexual dysfunction or GI problems

•   Also block histamine causing sedation

NaSSA Benefits / place in therapy •   Major depression, may help with SSRI induced sexual dysfunction •   Often added on to help with insomnia

–   low doses cause sedation, higher are stimulating and have AD effect •   Can be combined with other AD’s since different MOA •   Relatively safe in overdose

Cautions •   weight gain (blocks histamine), increased cholesterol, sedation,

Interactions •   Carbamazepine: decreases mirtazapine by 60%

Serotonin-2 Antagonists / Reuptake Inhibitors (SARI)

Example: trazodone (Desyrel)

•   exact mechanism unknown. Block presynaptic serotonin receptors

SARI Benefits / place in therapy •   Major depression, bipolar depression •   Usually added as sleep aid rather than

antidepressant – given at bedtime •   AD effects seen in 7-28 days

Cautions •   sedation/confusion, decreased BP, weight gain,

priapism •   Serotonin syndrome if combined with other AD’s

Monoamine Oxidase Inhibitors (MAOI) / Reversible Inhibitor of MAO-A (RIMA)

Example: phenelzine / moclobemide

•   MAOIs inhibit MAO – A/B enzyme responsible for breakdown of serotonin, NE, dopamine

•   MAOIs are irreversible, need 2 week washout •   RIMAs reversibly inhibit MAO-A (in brain) but do

not effect MAO-B (effect worn of in 24 hours) •   Usually reserved for resistant depression – don’t

see very often

MAOI / RIMA Tyramine: presser agent found in foods

–   Increases BP; broken down by MAO-B in gut •   Avoid tyramine rich foods if taking MAOI (RIMA ok), eg

meat, cheese •   Caution if hypertension or hyperthyroid •   Side effects :insomnia or sedation, increased stimulation,

nausea, wt loss or gain Interactions •   AD’s: Avoid unless moclobemide •   Narcotics esp meperidine: serotonergic rxn, restlessness •   Sympathomimetics: increase BP •   Triptans: serotonin syndrome

Adverse effects of antidepressants

Mechanism Side Effect Anticholinergic

Dry mouth, blurry vision, urinary retention, constipation, toxic confusional state, tachycardia

Antihistaminic Sedation Adrenergic/autonomic Excitement, tremor, palpitations, cardiac

arrythmias, orthostatic hypotension, hypertensive crisis (cheese effect)

Serotonergic Sedation, restlessness, sexual dysfunction

Unknown Weight gain

Antidepressants

How long to treat? •   General guideline:

–  1st episode: 1 year –  2nd episode: 2 years –  3rd episode: 5 years – can be lifelong

Antipsychotics

•   1st generation antipsychotics block presynaptic dopamine receptors

•   2nd generation antipsychotics block dopamine and serotonin

Antipsychotics

Dopamine Tract Origin Function Dopamine Antagonist Effect

Nigrostriatal Substantia nigra Extrapyramidal system, movement

Movement disorders

Mesolimbic Midbrain ventral tegmentum (terminates in limbic system)

Arousal, memory, stimulus processing, motivational behaviour

Relief of psychosis

Mesocortical Midbrain ventral tegmentum (terminates in cerebral cortex)

Cognition, motivation, emotional response

Negative symptoms (avolition, alogia, flat affect)

Tuberoinfundibular Hypothalamus Regulates prolactin release

Increased prolactin concentrations

Antipsychotics 1st generation

•   First type of medication used to treat psychosis •   Effective against positive symptoms of

psychosis: hallucinations, delusions, disorganized speech / behaviour

•   Little benefit for negative symptoms: Affective flattening, alogia, avolition, anhedonia

•   Non compliance is a problem: lots of side effects •   Depot (long acting) formulations are available

Antipsychotics 1st generation

Antipsychotic Dose equivalent Potency Chlorpromazine Thioridazine Methotrimeprazine Zuclopenthixol Loxapine Perphenazine Trifluperazine Fluphenazine Flupenthixol Thiothixene Haloperidol Pimozide

100mg 100mg 70mg 25mg 15mg 10mg 5mg 5mg 3mg 3mg 2mg 1mg

Low Intermediate High

Antipsychotics 1st generation

Low potency •   Higher doses •   Anticholinergic side effects: blurred vision, dry

mouth, urinary retention, weight gain

High potency •   Lower doses •   Neurological side effects (EPS): dystonia,

parkinsonism, akathesia, tardive dyskinesia, neuroleptic malignant syndrome

Managing neurological side effects

Dopamine Acetylcholine

Managing neurological side effects

•   Neurological side effects are due to blocking to much dopamine in the Substantia nigra

•   Treated using anticholinergic medications such as benztropine (restore balance)

•   Neuroleptic malignant syndrome!

Antipsychotics 2nd Generation Looser binding to dopamine receptors •   Less neurological side effects •   Less prolactin elevation Block 5HT2a •   Increased dopamine release in mesocortical system

(reduced negative symptoms) •   Negligible effect in mesolimbic system (dopamine

blockade predominates – reduced positive symptoms)

Antipsychotics 2nd Generation

Clozapine •   Most effective for treatment resistant patients •   Less risk of neurological side effects •   Very sedating, anticholinergic ++ weight gain •   May reduce seizure threshold •   Agranulocytosis

–   Incidence 1-2% however can be fatal –  Mandatory blood work, CSAN enrollment

Antipsychotics 2nd Generation

Olanzapine •   Block histamine – weight gain, dyslipidemia,

blood glucose disturbances •   Can be sedating

Quetiapine •   Less weight gain, but still occurs •   Large dosage range – smaller doses used for

anxiety or to help sleep

Antipsychotics 2nd Generation

Risperidone •   Most potent of 2nd generation •   Still raises prolactin levels •   Can cause EPS (but less than 1st generation) •   Less weight gain than olanzapine and clozapine •   Depot form available: improved compliance

Antipsychotics 2nd Generation

Ziprasidone •   Less likely to cause metabolic side effects such

as weight gain, or high cholesterol •   Good option for patients gaining weight on other

antipsychotics •   Can increase QTc interval – caution with cardiac

patients, or with other meds that can increase interval eg. haloperidol

Antipsychotics 2nd Generation

Aripiprazole •   D2 partial agonist •   Crowds out excess dopamine •   Reduced effect of excessive dopamine and

avoids side effects of too little

Mood Stabilizers

How do Mood Stabilizers Work? •   Neurotransmitter Theories

–   Lithium increases 5HT receptor sensitivity, inhibits release of dopamine, and enhances GABA activity

•   Sensitization and Kindling Theories –   Carbamazepine and valproic acid inhibit kindling in the CNS

•   Membrane and Cation Theories –   Abnormal calcium and sodium levels affect the synthesis of

neurotransmitters. Many antimania drugs have calcium antagonist effects and block cation transports in the membrane

•   Secondary Messenger Theories –   cAMP (cyclic adenosine monophosphate) systems are involved

in regulation neuronal regulation and play a role in the pathophysiology of bipolar disorder. Lithium normalizes G protein functioning

Real Answer

We are not sure

History of Lithium

•   Lithium is a univalent cation of the white metal series, closely related to both sodium and potassium

•   Lithium has been used for a variety of ailments such as epilepsy, gout, arthritis, and treatment of mania.

•   Approved for both treatment of acute mania and maintenance therapy (different target concentrations)

Dosing of Lithium •   Lithium therapy requires reaching therapeutic plasma

concentrations that are relatively close to toxic concentrations •   Administration of lithium requires 10-14 days before complete effect

is observed therefore acute mania is often treated in combination with an antipsychotic or added afterwards

•   Dosing of lithium ranges from 300mg a day to 1800mg a day with a usual range of 600 to 1200mg a day.

•   Concentrations from 1.5-2.0 mmol/L lead to increased drowsiness, ataxia, slurred speech, hypertonicity, and increasing tremor

•   Concentrations above 2.0 mmol/L can cause arrhythmia, decreased heart rate, myocarditis, seizures, coma, and death

Lithium Target Dose Target Concentrations Acute Mania 900-2400 mg/day 0.8-1.5 mmol/L

Maintenance Therapy 600-1800 mg/day 0.6-1.2 mmol/L

Lithium and the kidneys •   Lithium reduces the ability to concentrate urine

by interfering with the signalling of ADH (vasopressin) leading to increased permeability. This leads to large quantities of dilute urine, polyuria, and excessive thirst

•   Nephrogenic diabetes insipidius may result •   May lead to excessive loss of electrolytes and

electrolyte imbalances •   Long term use may result in permanent damage

and pathological changes to the kidney (glomerulosclerosis, tubular atrophy, and interstitial nephritis). Though this is controversial.

Other major side effects of lithium •   Hypothyroidism

–   Like iodide, lithium inhibits thyroid hormone (TH) release –   Lithium blocks the release of TH from the thyroid cells and

inhibits conversion of T4 to T3 –   This can lead to conditions like goiter and hyperparathyroidism –   Weight gain

•   Alopecia •   Acne •   Tremors

–   May be dose related •   Polyuria and Polydipsia are common

–   May have to check lithium levels and electrolyte levels or stop drug

•   General weakness, drowsiness, and cognitive blunting •   High chance of GI effects

–   Nausea (50%), Vomiting (20%), Diarrhea (20%)

Valproic acid •   Valproic acid (by its official name 2-propylvaleric

acid) was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian root

•   In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid

•   Approved for use in the treatment of bipolar disorder, seizures, and migraines

•   Dosages range from 250mg to 3000mg a day

Side effects of valproic acid Common side Effects •   GI side effects

–   Nausea, vomiting, diarrhea •   Sedation and fatigue •   Tremor •   Ataxia •   Alopecia/ changes in texture or color of hair/ hirsutism •   Menstrual disturbances

–   Caution in patients with Polycystic Ovary Syndrome •   the Weight gain

–   Mean increase of 8-14kg –   More common in women

Carbamazepine

•   Carbamazepine was discovered by chemist Walter Schindler at Geigy (now part of Novartis) in Basel, Switzerland in 1953

•   Approved for treatment in epilepsy, trigeminal neuralgia, and bipolar disorder

•   Also used for neuropathic pain •   Doses usually range from 200-800mg daily

Side effects of carbamazepine •   Lots of drug interactions!!

–   Very potent inducer of CYP 3A4 enzymes –   Will induce its own metabolism thus careful titration needed

•   Nausea/Vomiting •   Headache •   Dizziness/Incoordination/Vertigo •   Diplopia •   SIADH (Syndrome of Inappropriate Antidiuretic Hormone)

–   Common in the elderly •   Rash

–   Can be symptom of severe skin reaction

•   Rarely: –   Blood Dyscrasias

Topirimate

•   Launched in 1997, is marketed as Topamax

•   Is indicated in the treatment of epilepsy and migraines

•   Has off label indications for mood stabilization and weight loss

•   Usual dose ranges from 200-400mg daily

Side Effects

•   Nausea/Dizziness •   Cognitive Dysfunction •   Tremor •   Metabolic Acidosis •   Nephrolithiasis •   Hyperthermia •   Glaucoma •   Headache

Lamotrigine

•   Launched in 1994 and marketed as Lamictal

•   Approved in the treatment of epilepsy •   Off label indication for mood stabilization

and possibly depression

Side Effects

•   Rash –  Can possible be severe, careful titration

necessary •   Dizziness/Nausea/Vomiting •   Headache •   Diplopia •   Ataxia

Issues – Drug interactions

Can be pharmacokinetic or pharmacodynamic •   Pharmacokinetic

–   Affecting absorption ex. levofloxacin + calcium –   Affecting distribution ex. ASA + phenytoin –   Affecting metabolism ex. paroxetine + risperidone –   Affecting elimination ex. lithium + ibuprofen

•   Pharmacodynamic –   Alter the therapeutic effect of another drug ex.

levodopa + haloperidol

Issues – medications affecting presentation

Psychosis •   Illicit drug use – cocaine •   Withdrawal - opioids •   Pharmacotherapy – prednisone, mefloquine Depression •   Alcohol •   Betablockers – propranolol Insomnia •   Caffeine •   Buproprion Delerium •   Anticholinergic meds ex Gravol •   Narcotics / sedatives

Issues – medical conditions affecting presentation, do we treat? Example - depression •   Hypothyroid

–   Low thyroid function causes decrease in energy level often presenting as depression (check TSH level)

–   Treat with thyroid supplement (levothyroxine) –   Although it may take several months to completely normalize

thyroid function, depressive symptoms usually improve more rapidly and additional treatment is not necessary

•   Myocardial Infarction –   Many patients experience depressive symptoms following an MI –   Short term therapy with an antidepressent may be indicated

•   Depression of chronic disease –   Many diseases are associated with depression ex. AIDS, PD –   Often long term treatment with an antidepressent is indicated

Issues – medical conditions affecting presentation, do we treat? Example – psychosis •   CNS infection

–   obtain culture or treat empirically with anti infective agents –   Short term fast acting antipsychotics may be necessary to control

psychosis or agitation •   Fluid / electrolyte abnormalities

–   Obtain lab values and treat with appropriate supplementation –   Short term antipsychotics may be necessary

•   Dementia –   2nd generation antipsychotics are 1st line –   Use very small doses in elderly (increase mortality risk) –   Avoid use in Dementia with Lewy bodies

•   Antipsychotic sensitivity syndrome •   Worsening of early parkinsonism

Effects of Psychiatric medication on medical problems

Many drugs can either worsen a medical condition, or require dose adjustments in certain circumstances

•   Kidneys –   Lithium may adversely affect kidney function – serum

creatinine should be monitored at baseline and periodically throughout treatment

–   Lower doses should be used when initiating treatment with risperidal, and cautious titration is necessary

Effects of Psychiatric medication on medical problems

•   Heart –   All antipsychotics can cause QT prolongation –   Ziprasidone may cause the most QT prolongation and

cardiac toxicity – recommend baseline ECG and close monitoring

•   Blood pressure –   Venlafaxine can increase blood pressure – avoid in

hypertensive patients (unless well controlled) and monitor periodically during therapy

Issues – long term effects of psychotropic medications

•   Neurologic effects –  Common with older antipsychotics –  eg. Tardive dyskinesia (may be permanent)

•   Metabolic effects –  Common with newer antipsychotics –  Weight gain, impaired glucose tolerance,

elevated cholesterol levels: increase risk of diabetes & cardiovascular disease

Issues – long term effects of psychotropic medications

•   Although it is necessary to effectively treat mental illness in order to improve a patients safety and quality of life, we can’t ignore the implications of treatment – preventative measures for adverse outcomes should be utilized when treatment is started