Psychopharmacology in Psychopharmacology in Mood DisordersMood Disorders

AntidepressantsAntidepressants

AntidepressantsAntidepressants

Indications: Unipolar and bipolar Indications: Unipolar and bipolar depression, organic mood disorders, depression, organic mood disorders, schizoaffective disorder, anxiety disorders schizoaffective disorder, anxiety disorders including OCD, panic, social phobia, including OCD, panic, social phobia, PTSD, premenstrual dysphoric disorder PTSD, premenstrual dysphoric disorder and impulsivity associated with personality and impulsivity associated with personality disorders.disorders.

General guidelines for General guidelines for antidepressant useantidepressant use

Antidepressant efficacy is similar so selection is Antidepressant efficacy is similar so selection is based on past history of a response, side effect based on past history of a response, side effect profile and coexisting medical conditions.profile and coexisting medical conditions.

There is a delay typically of 3-6 weeks after a There is a delay typically of 3-6 weeks after a therapeutic dose is achieved before symptoms therapeutic dose is achieved before symptoms improve.improve.

If no improvement is seen after a trial of If no improvement is seen after a trial of adequate length (at least 2 months) and adequate length (at least 2 months) and adequate dose, either switch to another adequate dose, either switch to another antidepressant or augment with another agent. antidepressant or augment with another agent.

Antidepressant ClassificationsAntidepressant Classifications

Tricyclics (TCAs)Tricyclics (TCAs) Monoamine Oxidase Inhibitors (MAOIs)Monoamine Oxidase Inhibitors (MAOIs) Selective Serotonin Reuptake Inhibitors Selective Serotonin Reuptake Inhibitors

(SSRIs)(SSRIs) Serotonin/Norepinephrine Reuptake Serotonin/Norepinephrine Reuptake

Inhibitors (SNRIs)Inhibitors (SNRIs) Novel antidepressantsNovel antidepressants

TCAsTCAs

Very effective but potentially Very effective but potentially unacceptable side effect unacceptable side effect profile i.e. antihistaminic, profile i.e. antihistaminic, anticholinergic, anticholinergic, antiadrenergic antiadrenergic

Lethal in overdose (even a Lethal in overdose (even a one week supply can be one week supply can be lethal!)lethal!)

Can cause QT lengthening Can cause QT lengthening even at a therapeutic serum even at a therapeutic serum levellevel

Tertiary TCAsTertiary TCAs Have tertiary amine side chains Have tertiary amine side chains Side chains are prone to cross react with other types of Side chains are prone to cross react with other types of

receptors which leads to more side effects including receptors which leads to more side effects including antihistaminic (sedation and weight gain), anticholinergic antihistaminic (sedation and weight gain), anticholinergic (dry mouth, dry eyes, constipation, memory deficits and (dry mouth, dry eyes, constipation, memory deficits and potentially delirium), antiadrenergic (orthostatic potentially delirium), antiadrenergic (orthostatic hypotension, sedation, sexual dysfunction)hypotension, sedation, sexual dysfunction)

Act predominantly on serotonin receptorsAct predominantly on serotonin receptors Examples:Imipramine, amitriptyline, doxepin, Examples:Imipramine, amitriptyline, doxepin,

clomipramineclomipramine Have active metabolites including desipramine and Have active metabolites including desipramine and

nortriptylinenortriptyline

Secondary TCAsSecondary TCAs

Are often metabolites of tertiary aminesAre often metabolites of tertiary amines Primarily block norepinephrinePrimarily block norepinephrine Side effects are the same as tertiary TCAs Side effects are the same as tertiary TCAs

but generally are less severebut generally are less severe Examples: Desipramine, notrtriptylineExamples: Desipramine, notrtriptyline

Monoamine Oxidase Inhibitors Monoamine Oxidase Inhibitors (MAOIs)(MAOIs)

Bind irreversibly to monoamine oxidase thereby Bind irreversibly to monoamine oxidase thereby preventing inactivation of biogenic amines such preventing inactivation of biogenic amines such as norepinephrine, dopamine and serotonin as norepinephrine, dopamine and serotonin leading to increased synaptic levels.leading to increased synaptic levels.

Are very effective for depressionAre very effective for depression Side effects include orthostatic hypotension, Side effects include orthostatic hypotension,

weight gain, dry mouth, sedation, sexual weight gain, dry mouth, sedation, sexual dysfunction and sleep disturbancedysfunction and sleep disturbance

Hypertensive crisis can develop when MAOIHypertensive crisis can develop when MAOI’’s s are taken with tyramine-rich foods or are taken with tyramine-rich foods or sympathomimetics. sympathomimetics.

MAOIs cont.MAOIs cont.

Serotonin Syndrome can develop if take MAOI Serotonin Syndrome can develop if take MAOI with meds that increase serotonin or have with meds that increase serotonin or have sympathomimetic actions. Serotonin syndrome sympathomimetic actions. Serotonin syndrome sx include abdominal pain, diarrhea, sweats, sx include abdominal pain, diarrhea, sweats, tachycardia, HTN, myoclonus, irritability, tachycardia, HTN, myoclonus, irritability, delirium. Can lead to hyperpyrexia, delirium. Can lead to hyperpyrexia, cardiovascular shock and death.cardiovascular shock and death.

To avoid need to wait 2 weeks before switching To avoid need to wait 2 weeks before switching from an SSRI to an MAOI. The exception of from an SSRI to an MAOI. The exception of fluoxetine where need to wait 5 weeks because fluoxetine where need to wait 5 weeks because of long half-life.of long half-life.

SSRIsSSRIs

Selective Serotonin Reuptake Selective Serotonin Reuptake Inhibitors (SSRIs)Inhibitors (SSRIs)

Block the presynaptic serotonin reuptakeBlock the presynaptic serotonin reuptake Treat both anxiety and depressive sxTreat both anxiety and depressive sx Most common side effects include GI upset, Most common side effects include GI upset,

sexual dysfunction (30%+!), anxiety, sexual dysfunction (30%+!), anxiety, restlessness, nervousness, insomnia, fatigue or restlessness, nervousness, insomnia, fatigue or sedation, dizzinesssedation, dizziness

Very little risk of cardiotoxicity in overdoseVery little risk of cardiotoxicity in overdose Can develop a discontinuation syndrome with Can develop a discontinuation syndrome with

agitation, nausea, disequilibrium and dysphoria agitation, nausea, disequilibrium and dysphoria

Paroxetine (Paxil)Paroxetine (Paxil)

ProsPros Short half life with no active metabolite means no Short half life with no active metabolite means no

build-up (which is good if hypomania develops)build-up (which is good if hypomania develops) Sedating properties (dose at night) offers good initial Sedating properties (dose at night) offers good initial

relief from anxiety and insomniarelief from anxiety and insomnia

ConsCons Significant CYP2D6 inhibitionSignificant CYP2D6 inhibition Sedating, wt gain, more anticholinergic effectsSedating, wt gain, more anticholinergic effects Likely to cause a discontinuation syndromeLikely to cause a discontinuation syndrome

Sertraline (Zoloft)Sertraline (Zoloft)

ProsPros Very weak P450 interactions (only slight CYP2D6)Very weak P450 interactions (only slight CYP2D6) Short half life with lower build-up of metabolitesShort half life with lower build-up of metabolites Less sedating when compared to paroxetineLess sedating when compared to paroxetine

ConsCons Max absorption requires a full stomachMax absorption requires a full stomach Increased number of GI adverse drug reactions Increased number of GI adverse drug reactions

Fluoxetine (Prozac)Fluoxetine (Prozac)

ProsPros Long half-life so decreased incidence of discontinuation Long half-life so decreased incidence of discontinuation

syndromes. Good for pts with medication noncompliance issuessyndromes. Good for pts with medication noncompliance issues Initially activating so may provide increased energy Initially activating so may provide increased energy Secondary to long half life, can give one 20mg tab to taper Secondary to long half life, can give one 20mg tab to taper

someone off SSRI when trying to prevent SSRI Discontinuation someone off SSRI when trying to prevent SSRI Discontinuation SyndromeSyndrome

ConsCons Long half life and active metabolite may build up (e.g. not a good Long half life and active metabolite may build up (e.g. not a good

choice in patients with hepatic illness)choice in patients with hepatic illness) Significant P450 interactions so this may not be a good choice in Significant P450 interactions so this may not be a good choice in

pts already on a number of medspts already on a number of meds Initial activation may increase anxiety and insomniaInitial activation may increase anxiety and insomnia More likely to induce mania than some of the other SSRIsMore likely to induce mania than some of the other SSRIs

Citalopram (Celexa)Citalopram (Celexa)

ProsPros Low inhibition of P450 enzymes so fewer drug-drug Low inhibition of P450 enzymes so fewer drug-drug

interactions interactions Intermediate ½ life Intermediate ½ life

ConsCons Dose-dependent QT interval prolongation with doses Dose-dependent QT interval prolongation with doses

of 10-30mg daily- due to this risk doses of >40mg/day of 10-30mg daily- due to this risk doses of >40mg/day not recommended!not recommended!

Can be sedating (has mild antagonism at H1 Can be sedating (has mild antagonism at H1 histamine receptor)histamine receptor)

GI side effects (less than sertraline)GI side effects (less than sertraline)

Escitalopram (Lexapro)Escitalopram (Lexapro)

ProsPros Low overall inhibition of P450s enzymes so fewer Low overall inhibition of P450s enzymes so fewer

drug-drug interactionsdrug-drug interactions Intermediate 1/2 lifeIntermediate 1/2 life More effective than Citalopram in acute response More effective than Citalopram in acute response

and remissionand remission ConsCons

Dose-dependent QT interval prolongation with Dose-dependent QT interval prolongation with doses of 10-30mg dailydoses of 10-30mg daily

Nausea, headacheNausea, headache

Fluvoxamine (Luvox)Fluvoxamine (Luvox)

ProsPros Shortest ½ lifeShortest ½ life Found to possess some analgesic propertiesFound to possess some analgesic properties

ConsCons Shortest ½ lifeShortest ½ life GI distress, headaches, sedation, weaknessGI distress, headaches, sedation, weakness Strong inhibitor of CYP1A2 and CYP2C19Strong inhibitor of CYP1A2 and CYP2C19

Serotonin/Norepinephrine reuptake Serotonin/Norepinephrine reuptake inhibitors (SNRIs)inhibitors (SNRIs)

Inhibit both serotonin Inhibit both serotonin and noradrenergic and noradrenergic reuptake like the TCAS reuptake like the TCAS but without the but without the antihistamine, antihistamine, antiadrenergic or antiadrenergic or anticholinergic side anticholinergic side effectseffects

Used for depression, Used for depression, anxiety and possibly anxiety and possibly neuropathic painneuropathic pain

Venlafaxine (Effexor)Venlafaxine (Effexor) ProsPros

Minimal drug interactions and almost no P450 activityMinimal drug interactions and almost no P450 activity Short half life and fast renal clearance avoids build-up (good for Short half life and fast renal clearance avoids build-up (good for

geriatric populations)geriatric populations) ConsCons

Can cause a 10-15 mmHG dose dependent increase in diastolic Can cause a 10-15 mmHG dose dependent increase in diastolic BP.BP.

May cause significant nausea, primarily with immediate-release May cause significant nausea, primarily with immediate-release (IR) tabs(IR) tabs

Can cause a bad discontinuation syndrome, and taper Can cause a bad discontinuation syndrome, and taper recommended after 2 weeks of administrationrecommended after 2 weeks of administration

Noted to cause QT prolongationNoted to cause QT prolongation Sexual side effects in >30%Sexual side effects in >30%

Desvenlafaxine (Pristiq)Desvenlafaxine (Pristiq)

ProsPros Minimal drug interactionsMinimal drug interactions Short half life and fast renal clearance avoids Short half life and fast renal clearance avoids

build-up (good for geriatric populations)build-up (good for geriatric populations) ConsCons

GI distress in 20%+GI distress in 20%+ Dose related increase in total cholesterol, LDL Dose related increase in total cholesterol, LDL

and triglyceridesand triglycerides Dose related increase in BPDose related increase in BP

Duloxetine (Cymbalta)Duloxetine (Cymbalta)

ProsPros Some data to suggest efficacy for the physical Some data to suggest efficacy for the physical

symptoms of depressionsymptoms of depression Thus far less BP increase as compared to Thus far less BP increase as compared to

venlafaxine, however this may change in timevenlafaxine, however this may change in time ConsCons

CYP2D6 and CYP1A2 inhibitorCYP2D6 and CYP1A2 inhibitor Cannot break capsule, as active ingredient not Cannot break capsule, as active ingredient not

stable within the stomachstable within the stomach In pooled analysis had higher drop out rateIn pooled analysis had higher drop out rate

Novel antidepressants Novel antidepressants Mirtazapine (Remeron)Mirtazapine (Remeron)

ProsPros Different mechanism of action may provide a good augmentation Different mechanism of action may provide a good augmentation

strategy to SSRIs. Is a 5HT2 and 5HT3 receptor antagoniststrategy to SSRIs. Is a 5HT2 and 5HT3 receptor antagonist Can be utilized as a hypnotic at lower doses secondary to Can be utilized as a hypnotic at lower doses secondary to

antihistaminic effectsantihistaminic effects ConsCons

Increases serum cholesterol by 20% in 15% of patients and Increases serum cholesterol by 20% in 15% of patients and triglycerides in 6% of patientstriglycerides in 6% of patients

Very sedating at lower doses. At doses 30mg and above it can Very sedating at lower doses. At doses 30mg and above it can become activating and require change of administration time to become activating and require change of administration time to the morning.the morning.

Associated with weight gain (particularly at doses below 45mgAssociated with weight gain (particularly at doses below 45mg

Buproprion (Wellbutrin)Buproprion (Wellbutrin) ProsPros

Good for use as an augmenting agentGood for use as an augmenting agent Mechanism of action likely reuptake inhibition of dopamine and Mechanism of action likely reuptake inhibition of dopamine and

norepinephrine norepinephrine No weight gain, sexual side effects, sedation or cardiac interactionsNo weight gain, sexual side effects, sedation or cardiac interactions Low induction of maniaLow induction of mania Is a second line ADHD agent so consider if patient has a co-occurring Is a second line ADHD agent so consider if patient has a co-occurring

diagnosis diagnosis ConsCons

May increase seizure risk at high doses (450mg+) and should avoid in May increase seizure risk at high doses (450mg+) and should avoid in patients with Traumatic Brain Injury, bulimia and anorexia.patients with Traumatic Brain Injury, bulimia and anorexia.

Does not treat anxiety unlike many other antidepressants and can Does not treat anxiety unlike many other antidepressants and can actually cause anxiety, agitation and insomniaactually cause anxiety, agitation and insomnia

Has abuse potential because can induce psychotic sx at high dosesHas abuse potential because can induce psychotic sx at high doses

Mood StabilizersMood Stabilizers

Mood stabilizersMood stabilizers

Indications: Bipolar, cyclothymia, Indications: Bipolar, cyclothymia, schizoaffective, impulse control and schizoaffective, impulse control and intermittent explosive disorders.intermittent explosive disorders.

Classes: Lithium, anticonvulsants, Classes: Lithium, anticonvulsants, antipsychoticsantipsychotics

Which you select depends on what you Which you select depends on what you are treating and again the side effect are treating and again the side effect profile. profile.

LithiumLithium

Only medication to reduce suicide rate. Only medication to reduce suicide rate. Rate of completed suicide in BAD ~15%Rate of completed suicide in BAD ~15%

Effective in long-term prophylaxis of both mania Effective in long-term prophylaxis of both mania and depressive episodes in 70+% of BAD I ptsand depressive episodes in 70+% of BAD I pts

Factors predicting positive response to lithiumFactors predicting positive response to lithium Prior long-term response or family member with good Prior long-term response or family member with good

response response Classic pure maniaClassic pure mania Mania is followed by depressionMania is followed by depression

Lithium- how to use itLithium- how to use it

Before starting :Get baseline creatinine, TSH Before starting :Get baseline creatinine, TSH and CBC. In women check a pregnancy test- and CBC. In women check a pregnancy test- during the first trimester is associated with during the first trimester is associated with EbsteinEbstein’’s anomaly 1/1000 (20X greater risk than s anomaly 1/1000 (20X greater risk than the general population)the general population)

Monitoring: Steady state achieved after 5 days- Monitoring: Steady state achieved after 5 days- check 12 hours after last dose. Once stable check 12 hours after last dose. Once stable check q 3 months and TSH and creatinine q 6 check q 3 months and TSH and creatinine q 6 months. months.

Goal: blood level between 0.6-1.2Goal: blood level between 0.6-1.2

Lithium side effectsLithium side effects

Most common are GI distress including reduced Most common are GI distress including reduced appetite, nausea/vomiting, diarrheaappetite, nausea/vomiting, diarrhea

Thyroid abnormalitiesThyroid abnormalities Nonsignificant leukocytosisNonsignificant leukocytosis Polyuria/polydypsia secondary to ADH Polyuria/polydypsia secondary to ADH

antagonism. In a small number of patients can antagonism. In a small number of patients can cause interstitial renal fibrosis.cause interstitial renal fibrosis.

Hair loss, acneHair loss, acne Reduces seizure threshold, cognitive slowing, Reduces seizure threshold, cognitive slowing,

intention tremorintention tremor

Lithium toxicityLithium toxicity

Mild- levels 1.5-2.0 see vomiting, diarrhea, Mild- levels 1.5-2.0 see vomiting, diarrhea, ataxia, dizziness, slurred speech, ataxia, dizziness, slurred speech, nystagmus. nystagmus.

Moderate-2.0-2.5 nausea, vomiting, Moderate-2.0-2.5 nausea, vomiting, anorexia, blurred vision, clonic limb anorexia, blurred vision, clonic limb movements, convulsions, delirium, movements, convulsions, delirium, syncopesyncope

Severe- >2.5 generalized convulsions, Severe- >2.5 generalized convulsions, oliguria and renal failureoliguria and renal failure

AnticonvulsantsAnticonvulsants

Valproic acid (Depakote)Valproic acid (Depakote)

Valproic acid is as effective as Lithium in Valproic acid is as effective as Lithium in mania prophylaxis but is not as effective in mania prophylaxis but is not as effective in depression prophylaxis. depression prophylaxis.

Factors predicting a positive response:Factors predicting a positive response: rapid cycling patients (females>males)rapid cycling patients (females>males) comorbid substance issuescomorbid substance issues mixed patientsmixed patients Patients with comorbid anxiety disordersPatients with comorbid anxiety disorders

Better tolerated than LithiumBetter tolerated than Lithium

Valproic acidValproic acid

Before med is started: baseline liver Before med is started: baseline liver function tests (lfts), pregnancy test and function tests (lfts), pregnancy test and CBCCBC

Start folic acid supplement in womenStart folic acid supplement in women Monitoring: Steady state achieved after 4-Monitoring: Steady state achieved after 4-

5 days -check 12 hours after last dose and 5 days -check 12 hours after last dose and repeat CBC and lftsrepeat CBC and lfts

Goal: target level is between 50-125Goal: target level is between 50-125

Valproic acid side effectsValproic acid side effects

Thrombocytopenia and platelet Thrombocytopenia and platelet dysfunctiondysfunction

Nausea, vomiting, weight gainNausea, vomiting, weight gain TransaminitisTransaminitis Sedation, tremorSedation, tremor Increased risk of neural tube defect 1-2% Increased risk of neural tube defect 1-2%

vs 0.14-0.2% in general population vs 0.14-0.2% in general population secondary to reduction in folic acidsecondary to reduction in folic acid

Hair lossHair loss

Carbamazepine (Tegretol)Carbamazepine (Tegretol)

First line agent for acute mania and mania First line agent for acute mania and mania prophylaxisprophylaxis

Indicated for rapid cyclers and mixed Indicated for rapid cyclers and mixed patientspatients

Before med is started: baseline liver Before med is started: baseline liver function tests, CBC and an EKGfunction tests, CBC and an EKG

Monitoring: Steady state achieved after 5 Monitoring: Steady state achieved after 5 days -check 12 hours after last dose and days -check 12 hours after last dose and repeat CBC and lftsrepeat CBC and lfts

Goal: Target levels 4-12mcg/mlGoal: Target levels 4-12mcg/ml Need to check level and adjust dosing Need to check level and adjust dosing

after around a month because induces after around a month because induces own metabolism.own metabolism.

Carbamazepine side effectsCarbamazepine side effects

Rash- most common SE seenRash- most common SE seen Nausea, vomiting, diarrhea, transaminitisNausea, vomiting, diarrhea, transaminitis Sedation, dizziness, ataxia, confusionSedation, dizziness, ataxia, confusion AV conduction delaysAV conduction delays Aplastic anemia and agranulocytosis (<0.002%)Aplastic anemia and agranulocytosis (<0.002%) Water retention due to vasopressin-like effect Water retention due to vasopressin-like effect

which can result in hyponatremiawhich can result in hyponatremia Drug-drug interactions!Drug-drug interactions!

Drug interactionsDrug interactions Drugs that increase carbamazepine levels and/or toxicity: Drugs that increase carbamazepine levels and/or toxicity:

acetazolamide, cimetidine (both can cause rapid toxic reactions), acetazolamide, cimetidine (both can cause rapid toxic reactions), clozapine (may act synergistically to suppress BM), diltiazem, INH, clozapine (may act synergistically to suppress BM), diltiazem, INH, fluvoxamine, occasionally fluoxetine, erythromycin, clarithromycin, fluvoxamine, occasionally fluoxetine, erythromycin, clarithromycin, fluconazole, itraconazole, ketoconazole, metronidazole, fluconazole, itraconazole, ketoconazole, metronidazole, propoxyphene, verapamil, diltiazem.propoxyphene, verapamil, diltiazem.

Drugs that decrease carbamazepine levels: neuroleptics, Drugs that decrease carbamazepine levels: neuroleptics, barbiturates, phenytoin, TCAbarbiturates, phenytoin, TCA’’s.s.

VPA may increase or decrease carbamazepine levels.VPA may increase or decrease carbamazepine levels. Carbamazepine is a heteroinducer, increasing its own metabolism Carbamazepine is a heteroinducer, increasing its own metabolism

and that of many other drugs, including estrogen and progesterone and that of many other drugs, including estrogen and progesterone (contraceptives), warfarin, methadone, many psychotropics (contraceptives), warfarin, methadone, many psychotropics including antidepressants, antipsychotics, BZDincluding antidepressants, antipsychotics, BZD’’s, in addition to s, in addition to cyclosporine (and other immunosuppressants), theophylline, etc.cyclosporine (and other immunosuppressants), theophylline, etc.

Lamotrigine ( Lamictal)Lamotrigine ( Lamictal)

Indications similar to other anticonvulsantsIndications similar to other anticonvulsants Also used for neuropathic/chronic painAlso used for neuropathic/chronic pain Before med is started: baseline liver function Before med is started: baseline liver function

teststests Initiation/titration: start with 25 mg daily X 2 Initiation/titration: start with 25 mg daily X 2

weeks then increase to 50mg X 2 weeks then weeks then increase to 50mg X 2 weeks then increase to 100mg- faster titration has a increase to 100mg- faster titration has a higher incidence of serious rashhigher incidence of serious rash

If the patient stops the med for 5 days or more If the patient stops the med for 5 days or more have to start at 25mg again!have to start at 25mg again!

Lamotrigine: Side effectsLamotrigine: Side effects Nausea/vomitingNausea/vomiting Sedation, dizziness, ataxia and confusionSedation, dizziness, ataxia and confusion The most severe are toxic epidermal necrolysis and The most severe are toxic epidermal necrolysis and

Stevens Johnson's Syndrome. The character/severity of Stevens Johnson's Syndrome. The character/severity of the rash is not a good predictor of severity of reaction. the rash is not a good predictor of severity of reaction. Therefore, if Therefore, if ANYANY rash develops, discontinue use rash develops, discontinue use immediately.immediately.

Blood dyscrasias have been seen in rare cases.Blood dyscrasias have been seen in rare cases. Drugs that increase lamotrigine levels: Drugs that increase lamotrigine levels: VPA (doubles VPA (doubles

concentration, so use slower dose titration)concentration, so use slower dose titration),, sertraline.sertraline.

Antipsychotics as mood Antipsychotics as mood stabilizersstabilizers

Generic name Trade name Manic Mixed Maintenance Depressed

Aripiprazole Abilify x x xZiprasidone Geodon x x X*Risperdone Risperdal x xAsenapine Saphris x xQuetiapine Seroquel x X*Quetiapine XR Seroquel XR x X* xChlorpromazine Thorazine xOlanzapine Zyprexa x x xOlanzapine fluoxetine comb

Symbyax x

FDA approved indications in Bipolar disorder

*denotes FDA approval for adjunct therapy not *denotes FDA approval for adjunct therapy not mono-therapymono-therapy