1

Psychopharmacology in Psychopharmacology in PsychiatryPsychiatry

Heidi Combs, MDHeidi Combs, MD

Assistant Professor, University of Assistant Professor, University of Washington School of MedicineWashington School of Medicine

Faculty DisclosureFaculty Disclosure

I have no financial relationships to disclose I have no financial relationships to disclose relating to the subject matter of this relating to the subject matter of this presentationpresentation

Objectives: At the end of this Objectives: At the end of this session you should be able to:session you should be able to:

Identify general pharmacologic strategiesIdentify general pharmacologic strategiesDiscuss antidepressants including Discuss antidepressants including

indications for use and side effectsindications for use and side effectsDescribe mood stabilizers includingDescribe mood stabilizers includingDescribe mood stabilizers including Describe mood stabilizers including

indications for use and side effectsindications for use and side effectsReview antipsychotics including how to Review antipsychotics including how to

choose an antipsychotic and side effectschoose an antipsychotic and side effects Identify anxiolytic classes and indications Identify anxiolytic classes and indications

for usefor use

General Pharmacology strategiesGeneral Pharmacology strategies

Indication: Establish a diagnosis and identify Indication: Establish a diagnosis and identify the target symptoms that will be used to the target symptoms that will be used to monitor therapy response.monitor therapy response.

Choice of agent and dosage: Select anChoice of agent and dosage: Select anChoice of agent and dosage: Select an Choice of agent and dosage: Select an agent with an acceptable side effect profile agent with an acceptable side effect profile and use the lowest effective dose. and use the lowest effective dose. Remember the delayed response for many Remember the delayed response for many psych meds and drugpsych meds and drug--drug interactions.drug interactions.

Establish informed consent: The patient should Establish informed consent: The patient should understand the benefits and risks of the understand the benefits and risks of the medication. Make sure to document this medication. Make sure to document this discussion including pt understanding and discussion including pt understanding and agreement. In fertile women make sure to agreement. In fertile women make sure to document teratogenicity discussion.document teratogenicity discussion.

Implement a monitoring program: Track and Implement a monitoring program: Track and document compliance, side effects, target document compliance, side effects, target symptom response, blood levels and blood tests symptom response, blood levels and blood tests as appropriate.as appropriate.

Management: Adjust dosage for optimum Management: Adjust dosage for optimum benefit, safety and compliance. Use benefit, safety and compliance. Use adjunctive and combination therapies if adjunctive and combination therapies if needed however always strive for theneeded however always strive for theneeded however always strive for the needed however always strive for the simplest regimen. Keep your therapeutic simplest regimen. Keep your therapeutic endpoint in mind.endpoint in mind.

2

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 phobiaincluding OCD panic social phobiaincluding 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 3There is a delay typically of 3--6 weeks after a 6 weeks after a therapeutic dose is achieved before symptomstherapeutic dose is achieved before symptomstherapeutic 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 (SSRI )(SSRI )(SSRIs)(SSRIs)

Serotonin/Norepinephrine Reuptake Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)Inhibitors (SNRIs)

Novel antidepressantsNovel antidepressants

TCAsTCAs

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

t ti ll d li i ) ti d i ( th t tit ti ll d li i ) ti d i ( th t tipotentially 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

3

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 b t ll lb t ll lbut 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 depressiony py p 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 tyramineare taken with tyramine--rich foods or 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 irritabilitytachycardia HTN myoclonus irritabilitytachycardia, 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 halfof long half--life.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,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

buildbuild--up (which is good if hypomania develops)up (which is good if hypomania develops)

Sedating properties (dose at night) offers good initial Sedating properties (dose at night) offers good initial li f f i t d i ili f f i t d i irelief from anxiety and insomniarelief from anxiety and insomnia

ConsCons Significant CYP2D6 inhibitionSignificant CYP2D6 inhibition

Sedating, Sedating, wtwt gain, more anticholinergic effectsgain, more anticholinergic effects

Likely to cause a discontinuation syndromeLikely to cause a discontinuation syndrome

4

Sertraline (Zoloft)Sertraline (Zoloft)

ProsPros Very weak P450 interactions (only slight CYP2D6)Very weak P450 interactions (only slight CYP2D6)

Short half life with lower buildShort half life with lower build--up of metabolitesup 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 halfLong half--life so decreased incidence of discontinuation 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 SyndromeSyndromeSyndromeSyndrome

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 drugLow inhibition of P450 enzymes so fewer drug--drug drug interactions interactions

Intermediate ½ life Intermediate ½ life

CC ConsCons

DoseDose--dependent QT interval prolongation with doses dependent QT interval prolongation with doses of 10of 10--30mg daily30mg daily-- due to this risk doses of >40mg/day 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 Low overall inhibition of P450s enzymes so

fewer drugfewer drug--drug interactionsdrug interactions

Intermediate 1/2 lifeIntermediate 1/2 life Intermediate 1/2 lifeIntermediate 1/2 life

More effective than Citalopram in acute More effective than Citalopram in acute response and remissionresponse and remission

ConsCons DoseDose--dependent QT interval prolongation with dependent QT interval prolongation with

doses of 10doses of 10--30mg daily30mg daily

Nausea, headacheNausea, headache

Fluvoxamine (Fluvoxamine (LuvoxLuvox))

ProsPros Shortest ½ lifeShortest ½ life

Found to possess some analgesic propertiesFound to possess some analgesic properties

CCConsCons 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 reuptake like the TCAS but without the TCAS 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

5

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 buildShort half life and fast renal clearance avoids build--up (good for up (good for

geriatric populations)geriatric populations)

ConsConsC 10C 10 1515 HGHG d d d t i i di t lid d d t i i di t li Can cause a 10Can cause a 10--15 15 mmHGmmHG dose dependent increase in diastolic dose dependent increase in diastolic BP.BP.

May cause significant nausea, primarily with immediateMay cause significant nausea, primarily with immediate--release 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 buildbuild--up (good for geriatric populations)up (good for geriatric populations)buildbuild--up (good for geriatric populations)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 toThus far less BP increase as compared to 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 Cannot break capsule, as active ingredient not stable within the stomachnot stable 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 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

BuproprionBuproprion ((WellbutrinWellbutrin)) 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 coIs a second line ADHD agent so consider if patient has a co--occurringoccurringIs a second line ADHD agent so consider if patient has a coIs a second line ADHD agent so consider if patient has a co occurring 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 Has abuse potential because can induce psychotic sxsx at high dosesat high doses

Case 1Case 1

Susie Q has a nonpsychotic unipolar depression Susie Q has a nonpsychotic unipolar depression with no history of hypomania or mania. She has with no history of hypomania or mania. She has depressed mood, hyperphagia, psychomotor depressed mood, hyperphagia, psychomotor retardation and hypersomnolence. What agent retardation and hypersomnolence. What agent would you like to use for her?would you like to use for her?

Establish dx: Major depressive disorderEstablish dx: Major depressive disorder

Target symptoms: depression, hyperphagia, Target symptoms: depression, hyperphagia, psychomotor retardation and hypersomnolence psychomotor retardation and hypersomnolence

6

For a treatment naive patient start with an For a treatment naive patient start with an SSRI.SSRI.

Using the side effect profile as a guide Using the side effect profile as a guide select an SSRI that is less sedating. Good select an SSRI that is less sedating. Good ggchoices would be Citalopram, Fluoxetine choices would be Citalopram, Fluoxetine or Sertraline. Buproprion would also have or Sertraline. Buproprion would also have been a reasonable choice given her been a reasonable choice given her hypersomnolence, psychomotor hypersomnolence, psychomotor retardation and hyperphagia. retardation and hyperphagia.

Less desirable choices include Paxil and Less desirable choices include Paxil and Mirtazapine because of sedation and wt Mirtazapine because of sedation and wt gain. gain.

Not a duel reuptake inhibitors because sheNot a duel reuptake inhibitors because sheNot a duel reuptake inhibitors because she Not a duel reuptake inhibitors because she is treatment naïve and may not need a is treatment naïve and may not need a ““big gunbig gun””. .

Not a TCA because of side effectsNot a TCA because of side effects

Case 2Case 2

Billy bob is a 55 year old diabetic man with mild Billy bob is a 55 year old diabetic man with mild HTN and painful diabetic neuropathy who has HTN and painful diabetic neuropathy who has had previous depressive episodes and one had previous depressive episodes and one suicide attempt. He meets criteria currently for a suicide attempt. He meets criteria currently for a major depressive episode with some anxiety. He major depressive episode with some anxiety. He has been treated with paroxetine, setraline and has been treated with paroxetine, setraline and buproprion. His depression was improved buproprion. His depression was improved slightly with each of these meds but never slightly with each of these meds but never remitted. What would you like to treat him with?remitted. What would you like to treat him with?

Case 2 continuedCase 2 continued

Establish dx: Major depressive disorder with Establish dx: Major depressive disorder with anxious featuresanxious features

Target symptoms: depressive sx, anxiety andTarget symptoms: depressive sx, anxiety and Target symptoms: depressive sx, anxiety and Target symptoms: depressive sx, anxiety and possibly his neuropathic painpossibly his neuropathic pain

Assuming he received adequate trials previously Assuming he received adequate trials previously would move on to a duel reuptake inhibitor as he would move on to a duel reuptake inhibitor as he had not achieved remission with two SSRIS or a had not achieved remission with two SSRIS or a novel agent.novel agent.

Case 2 continuedCase 2 continued

Given his mild HTN would not choose Given his mild HTN would not choose Venlafaxine. TCAVenlafaxine. TCA’’s can help with neuropathic s can help with neuropathic pain and depression however not a good choice pain and depression however not a good choice given the SE profile and lethality in overdose. given the SE profile and lethality in overdose. Duloxetine is a good choice since it has an Duloxetine is a good choice since it has an indication for neuropathic pain, depression and indication for neuropathic pain, depression and anxiety. Three birds with one stone!! anxiety. Three birds with one stone!!

Keep in mind Duloxetine is a CYP2D6 and Keep in mind Duloxetine is a CYP2D6 and CPY1A2 inhibitor and has potential drugCPY1A2 inhibitor and has potential drug--drug drug interactions.interactions.

Mood StabilizersMood Stabilizers

7

Mood stabilizersMood stabilizers

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

Classes: Lithium anticonvulsantsClasses: Lithium anticonvulsantsClasses: 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 longEffective in long--term prophylaxis of both mania term prophylaxis of both mania and depressive episodes in 70+% of BAD Iand depressive episodes in 70+% of BAD I ptsptsand depressive episodes in 70 % of BAD I and depressive episodes in 70 % of BAD I ptspts

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

response response

Classic pure maniaClassic pure mania

Mania is followed by depressionMania is followed by depression

LithiumLithium-- how to use ithow to use it

Before starting :Get baseline creatinine, TSH Before starting :Get baseline creatinine, TSH and CBC. In women check a pregnancy testand 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)the general population)the general population)

Monitoring: Steady state achieved after 5 daysMonitoring: 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 0.6Goal: blood level between 0.6--1.21.2

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

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

ModerateModerate--2.02.0--2.5 nausea, vomiting, 2.5 nausea, vomiting, , g,, g,anorexia, blurred vision, clonic limb anorexia, blurred vision, clonic limb movements, convulsions, delirium, movements, convulsions, delirium, syncopesyncope

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

AnticonvulsantsAnticonvulsants

8

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:p g p pp g p p 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 Start folic acid supplement in womenStart folic acid supplement in women

Monitoring: Steady state achieved after 4Monitoring: Steady state achieved after 4--5 days 5 days --check 12 hours after last dose and check 12 hours after last dose and repeat CBC and lftsrepeat CBC and lfts

Goal: target level is between 50Goal: target level is between 50--125125

Valproic acid side effectsValproic acid side effects

Thrombocytopenia and platelet Thrombocytopenia and platelet dysfunctiondysfunction

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

vs 0.14vs 0.14--0.2% in general population 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

I di t d f id l d i dI di t d f id l d i d 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 days --check 12 hours after last dose and check 12 hours after last dose and yyrepeat CBC and lftsrepeat CBC and lfts

Goal: Target levels 4Goal: Target levels 4--12mcg/ml12mcg/mlNeed 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

RashRash-- most common SE seenmost common SE seen

Nausea, vomiting, diarrhea, transaminitisNausea, vomiting, diarrhea, transaminitis

Sedation, dizziness, ataxia, confusionSedation, dizziness, ataxia, confusion

AV conduction delaysAV conduction delays AV conduction delaysAV conduction delays

Aplastic anemia and agranulocytosis (<0.002%)Aplastic anemia and agranulocytosis (<0.002%)

Water retention due to vasopressinWater retention due to vasopressin--like effect like effect which can result in hyponatremiawhich can result in hyponatremia

DrugDrug--drug interactions!drug interactions!

9

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, b bit t h t i TCAb bit t h t i TCA’’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 Before med is started: baseline liver function function teststests

Initiation/titration: start with 25 mg daily X Initiation/titration: start with 25 mg daily X 2 weeks then increase to 50mg X 2 weeks 2 weeks then increase to 50mg X 2 weeks then increase to 100mgthen increase to 100mg-- faster titration faster titration has a higher incidence of serious rashhas a higher incidence of serious rash

If the patient stops the med for 5 days or If the patient stops the med for 5 days or more have to start at 25mg again!more 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. g p yg p yTherefore, 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*

FDA approved indications in Bipolar disorder

Quetiapine Seroquel x XQuetiapine XR Seroquel XR x X* xChlorpromazine Thorazine xOlanzapine Zyprexa x x xOlanzapinefluoxetine comb

Symbyax x

*denotes FDA approval for adjunct therapy not *denotes FDA approval for adjunct therapy not monomono--therapytherapy

Case 3Case 3

33 33 yoyo woman hospitalized with her first woman hospitalized with her first episode of mania. She has no previous episode of mania. She has no previous history of a depressive episode. She has history of a depressive episode. She has no drug or ETOH history and has no no drug or ETOH history and has no medical issues. What medication would medical issues. What medication would you like to start?you like to start?

10

Given her first presentation was a manic Given her first presentation was a manic episode statistically she will do better on episode statistically she will do better on lithium.lithium.

Make sure to check a pregnancy testMake sure to check a pregnancy testMake sure to check a pregnancy test, Make sure to check a pregnancy test, serum creatinine and TSH prior to initiation serum creatinine and TSH prior to initiation of treatment.of treatment.

Discuss with her what she will use for birth Discuss with her what she will use for birth control and document this discussion.control and document this discussion.

You start her at 300mg BID (average You start her at 300mg BID (average starting dose) and when she comes to see starting dose) and when she comes to see you in one week she is complaining about you in one week she is complaining about stomach irritation and some diarrheastomach irritation and some diarrheastomach irritation and some diarrhea. stomach irritation and some diarrhea. What do you think is going on and what What do you think is going on and what should you do?should you do?

GI irritation including diarrhea is common GI irritation including diarrhea is common particularly early in treatment. Encourage particularly early in treatment. Encourage pt to drink adequate fluid, leave at current pt to drink adequate fluid, leave at current dose and see if side effects resolvedose and see if side effects resolvedose and see if side effects resolve.dose and see if side effects resolve.

Case 4Case 4

27 27 yoyo male is admitted secondary to a male is admitted secondary to a manic episode. In reviewing his history manic episode. In reviewing his history you find he has 5 to 6 manic or depressive you find he has 5 to 6 manic or depressive episodes a year. He has also struggled on episodes a year. He has also struggled on and off with ETOH abuse. What and off with ETOH abuse. What medication would you like to start?medication would you like to start?

Depakote would be a good choice Depakote would be a good choice because pt is a rapid cycler (4 or more because pt is a rapid cycler (4 or more depressive or manic episodes/year) and depressive or manic episodes/year) and because of comorbid ETOH abusebecause of comorbid ETOH abusebecause of comorbid ETOH abuse.because of comorbid ETOH abuse.

You start 250mg BID and titrate to 500mg You start 250mg BID and titrate to 500mg BID. His depakote level is 70. You check BID. His depakote level is 70. You check his lfts and compared to baseline they his lfts and compared to baseline they have increased as follows:have increased as follows:

ALT 48 ALT 48 115115

AST 62AST 62140140

ALK PHOS 32ALK PHOS 328080

What happened and what do you want to What happened and what do you want to do??do??

11

It is not unusual for patients on It is not unusual for patients on anticonvulsants to experience an increase anticonvulsants to experience an increase in lfts and as long as they do not more in lfts and as long as they do not more than triple no change in therapy isthan triple no change in therapy isthan triple no change in therapy is than triple no change in therapy is indicated. indicated.

Continue to monitor over timeContinue to monitor over time

AntipsychoticsAntipsychotics

Indications for use: schizophrenia, Indications for use: schizophrenia, schizoaffective disorder, bipolar disorderschizoaffective disorder, bipolar disorder--for mood stabilization and/or when for mood stabilization and/or when psychotic features are present deliriumpsychotic features are present deliriumpsychotic features are present, delirium, psychotic features are present, delirium, psychotic depression, dementia, psychotic depression, dementia, trichotillomania, augmenting agent in trichotillomania, augmenting agent in treatment resistant anxiety disorders. treatment resistant anxiety disorders.

Key pathways affected by Key pathways affected by dopamine in the Braindopamine in the Brain

MESOCORTICAMESOCORTICALL-- projects from the projects from the ventral ventral tegmentumtegmentum (brain stem) to the (brain stem) to the cerebral cortex. This pathway is felt to cerebral cortex. This pathway is felt to be where the negative symptoms andbe where the negative symptoms andbe where the negative symptoms and be where the negative symptoms and cognitive disorders (lack of executive cognitive disorders (lack of executive function) arise. Problem here for a function) arise. Problem here for a psychotic patient, is psychotic patient, is too little too little dopamine.dopamine.

MESOLIMBICMESOLIMBIC--projects from the projects from the dopaminergic cell bodies in the ventral dopaminergic cell bodies in the ventral tegmentum to the limbic system. This tegmentum to the limbic system. This pathway is where the positive symptomspathway is where the positive symptomspathway is where the positive symptoms pathway is where the positive symptoms come from (hallucinations, delusions, come from (hallucinations, delusions, and thought disorders). Problem here in and thought disorders). Problem here in a psychotic patient is there is a psychotic patient is there is too much too much dopamine.dopamine.

NIGROSTRIATALNIGROSTRIATAL-- projects from the projects from the dopaminergic cell bodies in the dopaminergic cell bodies in the substantia nigra to the basal ganglia. substantia nigra to the basal ganglia. This pathway is involved in movement This pathway is involved in movement regulation. Remember that dopamine regulation. Remember that dopamine suppresses acetylcholine activity. suppresses acetylcholine activity. Dopamine hypoactivityDopamine hypoactivity can cause can cause Parkinsonian movements i.e. rigidity, Parkinsonian movements i.e. rigidity, bradykinesia, tremors), akathisia and bradykinesia, tremors), akathisia and dystonia. dystonia.

12

TUBEROINFUNDIBULARTUBEROINFUNDIBULAR--projects from projects from the hypothalamus to the anterior the hypothalamus to the anterior pituitary. Remember that dopamine pituitary. Remember that dopamine release inhibits/regulates prolactinrelease inhibits/regulates prolactinrelease inhibits/regulates prolactin release inhibits/regulates prolactin release. Blocking dopamine in this release. Blocking dopamine in this pathway will predispose your patient to pathway will predispose your patient to hyperprolactinemia hyperprolactinemia (gynecomastia/galactorrhea/decreased (gynecomastia/galactorrhea/decreased libido/menstrual dysfunction).libido/menstrual dysfunction).

Antipsychotics: TypicalsAntipsychotics: Typicals

Are D2 dopamine receptor antagonistsAre D2 dopamine receptor antagonists

High potency typical antipsychotics bind to High potency typical antipsychotics bind to the D2 receptor with high affinity. As a the D2 receptor with high affinity. As a result they have higher risk ofresult they have higher risk ofresult they have higher risk of result they have higher risk of extrapyramidal side effects. Examples extrapyramidal side effects. Examples include Fluphenazine, Haloperidol, include Fluphenazine, Haloperidol, Pimozide.Pimozide.

Low potency typical antipsychotics have Low potency typical antipsychotics have less affinity for the D2 receptors but tend less affinity for the D2 receptors but tend to interact with nondopaminergic receptors to interact with nondopaminergic receptors resulting in more cardiotoxic andresulting in more cardiotoxic andresulting in more cardiotoxic and resulting in more cardiotoxic and anticholinergic adverse effects including anticholinergic adverse effects including sedation, hypotension. Examples include sedation, hypotension. Examples include chlorpromazine and Thioridazine. chlorpromazine and Thioridazine.

Antipsychotics: AtypicalsAntipsychotics: Atypicals

The Atypical Antipsychotics The Atypical Antipsychotics -- atypical atypical agents are serotoninagents are serotonin--dopamine 2 dopamine 2 antagonists (SDAs) antagonists (SDAs)

They are considered atypical in the wayThey are considered atypical in the way They are considered atypical in the way They are considered atypical in the way they affect dopamine they affect dopamine andand serotonin serotonin neurotransmission in the four key neurotransmission in the four key dopamine pathways in the brain. dopamine pathways in the brain.

Risperidone (Risperdal)Risperidone (Risperdal)

Available in regular tabs, IM depot forms and Available in regular tabs, IM depot forms and rapidly dissolving tablet rapidly dissolving tablet

Functions more like a typical antipsychotic at Functions more like a typical antipsychotic at doses greater than 6mgdoses greater than 6mgg gg g

Increased extrapyramidal side effects (dose Increased extrapyramidal side effects (dose dependent)dependent)

Most likely atypical to induce Most likely atypical to induce hyperprolactinemiahyperprolactinemia

Weight gain and sedation (dosage dependent)Weight gain and sedation (dosage dependent)

Olanzapine (Zyprexa)Olanzapine (Zyprexa)

Available in regular tabs, immediate release IM, Available in regular tabs, immediate release IM, rapidly dissolving tab, rapidly dissolving tab, depodepo formform

Weight gain (can be as much as 30Weight gain (can be as much as 30--50lbs with 50lbs with even short term use)even short term use)))

May cause hypertriglyceridemia, May cause hypertriglyceridemia, hypercholesterolemia, hyperglycemia (even hypercholesterolemia, hyperglycemia (even without weight gain)without weight gain)

May cause May cause hyperprolactinemiahyperprolactinemia (< (< risperidonerisperidone))

May cause May cause transaminitistransaminitis (2% of all patients)(2% of all patients)

13

Quetiapine (Seroquel)Quetiapine (Seroquel)

Available in a regular tablet form onlyAvailable in a regular tablet form only

May cause transaminitis (6% of all patients)May cause transaminitis (6% of all patients)

May be associated with weight gain, though less May be associated with weight gain, though less than seen with olanzapinethan seen with olanzapinethan seen with olanzapinethan seen with olanzapine

May cause hypertriglyceridemia, May cause hypertriglyceridemia, hypercholesterolemia, hyperglycemia (even hypercholesterolemia, hyperglycemia (even without weight gain), however less than without weight gain), however less than olanzapineolanzapine

Most likely to cause orthostatic hypotensionMost likely to cause orthostatic hypotension

Ziprasidone (Geodon)Ziprasidone (Geodon)

Available regular tabs and IM immediate Available regular tabs and IM immediate release formrelease form

Clinically significant QT prolongation in Clinically significant QT prolongation in susceptible patientssusceptible patientsp pp p

May cause hyperprolactinemia (< May cause hyperprolactinemia (< risperidone)risperidone)

No associated weight gainNo associated weight gain Absorption is increased (up to 100%) with Absorption is increased (up to 100%) with

foodfood

Aripiprazole (Abilify)Aripiprazole (Abilify)

Available in regular Available in regular tabs, tabs, immediate release IM immediate release IM formulation and formulation and depodepo formform

Unique mechanism of action as a D2 partial Unique mechanism of action as a D2 partial agonistagonistL EPS QT l ti l d tiL EPS QT l ti l d ti Low EPS, no QT prolongation, low sedationLow EPS, no QT prolongation, low sedation

CYP2D6 (fluoxetine and paroxetine), 3A4 CYP2D6 (fluoxetine and paroxetine), 3A4 (carbamazepine and ketoconazole) interactions (carbamazepine and ketoconazole) interactions that the manufacturer recommends adjusted that the manufacturer recommends adjusted dosing. Could cause potential intolerability due dosing. Could cause potential intolerability due to to akathisiaakathisia/activation./activation.

Not associated with weight gainNot associated with weight gain

Clozapine (Clozaril)Clozapine (Clozaril)

Available in 1 formAvailable in 1 form-- a regular tableta regular tablet Is reserved for treatment resistant patients because of Is reserved for treatment resistant patients because of

side effect profile but this stuff works!side effect profile but this stuff works! Associated with Associated with agranulocytosisagranulocytosis (0.5(0.5--2%) and therefore 2%) and therefore

requires weekly blood draws x 6 months, then Qrequires weekly blood draws x 6 months, then Q--2weeks x 6 months)2weeks x 6 months)2weeks x 6 months)2weeks x 6 months)

Increased risk of seizures (especially if lithium is also on Increased risk of seizures (especially if lithium is also on board)board)

Associated with the most sedation, weight gain and Associated with the most sedation, weight gain and transaminitistransaminitis

Increased risk of hypertriglyceridemia, Increased risk of hypertriglyceridemia, hypercholesterolemia, hyperglycemia, including hypercholesterolemia, hyperglycemia, including nonketoticnonketotic hyperosmolar coma and death with and/or hyperosmolar coma and death with and/or without weight gainwithout weight gain

IloperidoneIloperidone ((FanaptFanapt))

Comes in regular tabsComes in regular tabs Needs BID dosingNeeds BID dosing Titrate over 4 daysTitrate over 4 days to 12mg/day in order to minimize to 12mg/day in order to minimize

risk of orthostatic hypotension risk of orthostatic hypotension L EPSL EPS k thi ik thi i tt i d t b li di t bi d t b li di t b Low EPS, Low EPS, akathisiaakathisia, , wtwt gain and metabolic disturbancesgain and metabolic disturbances Inhibitors of 3A4Inhibitors of 3A4 (ketoconazole) (ketoconazole) or 2D6or 2D6 (fluoxetine, (fluoxetine,

paroxetine)paroxetine)--Can increase blood levels twoCan increase blood levels two--fold!fold! QT ProlongationQT Prolongation-- mean increase of 19msec at 12mg BIDmean increase of 19msec at 12mg BID Not recommended for patients with hepatic impairmentNot recommended for patients with hepatic impairment

Citrome L, Postgraduate Medicine Citrome L, Postgraduate Medicine 20112011

AsenapineAsenapine ((SaphrisSaphris)) Sublingual Sublingual (no food or liquid for 10 min)

BID dosing requiredBID dosing required

Can start at therapeutic doseCan start at therapeutic dose

LowLow wtwt gain and metabolic disturbancesgain and metabolic disturbances Low Low wtwt gain and metabolic disturbancesgain and metabolic disturbances

Sedation, somnolence, Sedation, somnolence, akathisiaakathisia

Not recommended for patients with severe Not recommended for patients with severe hepatic impairmenthepatic impairment

Be careful with coBe careful with co--administration of administration of ((CYP1A2 inhibitorCYP1A2 inhibitor) )

14

LurasidoneLurasidone ((latudalatuda))

Can dose once daily and start at therapeutic doseCan dose once daily and start at therapeutic dose No QT prolongation warningNo QT prolongation warning Less treatment emergent weight gain and metabolic Less treatment emergent weight gain and metabolic

disturbancesdisturbances MMust administer with food (>350kcals)ust administer with food (>350kcals) MMust administer with food ( 350kcals)ust administer with food ( 350kcals) Is associated with Is associated with akathisiaakathisia, sedation, sedation Dose should not exceed 40mg day in patients with Dose should not exceed 40mg day in patients with

moderate to severe renal or hepatic impairmentmoderate to severe renal or hepatic impairment Contraindicated coContraindicated co--administration with CYP 3A4 administration with CYP 3A4

inhibitors and inducers inhibitors and inducers

Leucht S, et al. Lancet 2009; 373(9657):31‐41. Slide courtesy of Dick Miyoshi 

Leucht S, et al. Lancet 2009; 373(9657):31‐41. Slide courtesy of Dick Miyoshi 

Antipsychotic adverse effectsAntipsychotic adverse effects

Tardive Dyskinesia (TD)Tardive Dyskinesia (TD)--involuntary muscle involuntary muscle movements that may not resolve with drug movements that may not resolve with drug discontinuationdiscontinuation-- risk approx. 5% per yearrisk approx. 5% per year

Neuroleptic Malignant Syndrome (NMS): Neuroleptic Malignant Syndrome (NMS): p g y ( )p g y ( )Characterized by severe muscle rigidity, fever, Characterized by severe muscle rigidity, fever, altered mental status, autonomic instability, altered mental status, autonomic instability, elevated WBC, CPK and lfts. Potentially fatal.elevated WBC, CPK and lfts. Potentially fatal.

Extrapyramidal side effects (EPS): Acute Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome, Akathisiadystonia, Parkinson syndrome, Akathisia

Agents for EPSAgents for EPS

Anticholinergics such as benztropine, Anticholinergics such as benztropine, trihexyphenidyl, diphenhydraminetrihexyphenidyl, diphenhydramine

Dopamine facilitators such as AmantadineDopamine facilitators such as Amantadine

B tB t bl k h l lbl k h l l BetaBeta--blockers such as propranolol blockers such as propranolol

Need to watch for anticholinergic SE Need to watch for anticholinergic SE particularly if taken with other meds with particularly if taken with other meds with anticholinergic activity ie TCAsanticholinergic activity ie TCAs

CaseCase

21 yo AA male with symptoms consistent 21 yo AA male with symptoms consistent with schizophrenia is admitted because of with schizophrenia is admitted because of profound psychotic sx. He is treatment profound psychotic sx. He is treatment naïve You plan to start an antipsychoticnaïve You plan to start an antipsychotic--naïve. You plan to start an antipsychoticnaïve. You plan to start an antipsychoticwhat baseline blood work would you what baseline blood work would you obtain?obtain?

15

Many atypical antipsychotics can cause Many atypical antipsychotics can cause dyslipidemia, dyslipidemia, transaminitistransaminitis and elevated and elevated blood sugars and there is a class risk of blood sugars and there is a class risk of diabetes unrelated to weight gain so youdiabetes unrelated to weight gain so youdiabetes unrelated to weight gain so you diabetes unrelated to weight gain so you need the following:need the following:

Fasting lipid profileFasting lipid profile

Fasting blood sugarFasting blood sugar

LftsLfts

CBCCBC

His labs come back as follows:His labs come back as follows:

Total Cholesterol:215 HDL:30 LDL:145Total Cholesterol:215 HDL:30 LDL:145

Glucose 88Glucose 88

LftsLfts, CBC WNL, CBC WNL

What agent would you like to start?What agent would you like to start?

Pt has mildly elevated total cholesterol and a low Pt has mildly elevated total cholesterol and a low HDL for his age. Would not choose Olanzapine HDL for his age. Would not choose Olanzapine or Quetiapine given risk of dyslipidemia. or Quetiapine given risk of dyslipidemia. Risperidone, Ziprasidone or Aripiprazole are Risperidone, Ziprasidone or Aripiprazole are good choices.good choices.

You start Risperidone and titrate to 3mg BID You start Risperidone and titrate to 3mg BID (high average dose). He starts to complain that (high average dose). He starts to complain that he he ““feels uncomfortable in my skin like I canfeels uncomfortable in my skin like I can’’t sit t sit stillstill””. What is likely going on and what are you . What is likely going on and what are you going to do about it?going to do about it?

He is likely experiencing akathisia. This is He is likely experiencing akathisia. This is not uncommon with Risperidone. Given he not uncommon with Risperidone. Given he was very ill reducing the dose may not be was very ill reducing the dose may not be the best choice so likely treat with anthe best choice so likely treat with anthe best choice so likely treat with an the best choice so likely treat with an anticholinergic agent or propranolol. You anticholinergic agent or propranolol. You need to treat akathisia because it is need to treat akathisia because it is associated with an increase risk for associated with an increase risk for suicide!suicide!

AnxiolyticsAnxiolytics

Used to treat many diagnoses including Used to treat many diagnoses including panic disorder, generalized Anxiety panic disorder, generalized Anxiety disorder, substancedisorder, substance--related disorders and related disorders and their withdrawal insomnias andtheir withdrawal insomnias andtheir withdrawal, insomnias and their withdrawal, insomnias and parasomnias. In anxiety disorders often parasomnias. In anxiety disorders often use anxiolytics in combination with SSRIS use anxiolytics in combination with SSRIS or SNRIs for treatment.or SNRIs for treatment.

Buspirone (Buspar)Buspirone (Buspar)

Pros: Pros: Good augmentation strategyGood augmentation strategy-- Mechanism of action is Mechanism of action is

5HT1A agonist. It works independent of endogenous 5HT1A agonist. It works independent of endogenous release of serotonin.release of serotonin.

N d tiN d ti No sedationNo sedation

Cons: Cons: Takes around 2 weeks before patients notice results.Takes around 2 weeks before patients notice results.

Will not reduce anxiety in patients that are used to Will not reduce anxiety in patients that are used to taking BZDs because there is no sedation effect to taking BZDs because there is no sedation effect to ““take the edge off.take the edge off.

16

BenzodiazapinesBenzodiazapines

Used to treat insomnia, parasomnias and Used to treat insomnia, parasomnias and anxiety disorders.anxiety disorders.

Often used for CNS depressant withdrawal Often used for CNS depressant withdrawal protocols ex. ETOH withdrawal.protocols ex. ETOH withdrawal.

Side effects/consSide effects/cons Side effects/consSide effects/cons SomnolenceSomnolence Cognitive deficitsCognitive deficits AmnesiaAmnesia DisinhibitionDisinhibition ToleranceTolerance DependenceDependence

DrugDrug

Dose Dose EquivaEquivalency lency (mg)(mg)

Peak BloodPeak BloodLevel Level

(hours)(hours)

Elimination Elimination HalfHalf--LifeLife1 1

(hours)(hours)CommentsComments

Alprazolam Alprazolam (Xanax)(Xanax)

0.50.511--22 1212--1515 Rapid oral absorptionRapid oral absorption

ChlordiazeChlordiazepoxide poxide (Librium)(Librium)

10.010.0

22--44 1515--4040

Active metabolites; Active metabolites; erratic erratic bioavailability bioavailability from IM from IM injectioninjection

Clonazepam Clonazepam (Klonopin)(Klonopin)

0.250.2511--44 1818--5050

Can have layering Can have layering effecteffect(Klonopin)(Klonopin) effecteffect

Diazepam Diazepam (Valium)(Valium)

5.05.0

11--22 2020--8080

Active metabolites; Active metabolites; erratic erratic bioavailability bioavailability from IM from IM injectioninjection

Flurazepam Flurazepam (Dalmane)(Dalmane)

30.030.011--22 4040--100100

Active metabolites Active metabolites with long halfwith long half--liveslives

Lorazepam Lorazepam (Ativan)(Ativan)

1.01.011--66 1010--2020 No active metabolitesNo active metabolites

Oxazepam Oxazepam (Serax)(Serax)

15.015.022--44 1010--2020 No active metabolitesNo active metabolites

Temazepam Temazepam (Restoril)(Restoril)

30.030.022--33 1010--4040 Slow oral absorptionSlow oral absorption

Triazolam Triazolam (Halcion)(Halcion)

0.250.2511

22--33

Rapid onset; short Rapid onset; short duration of duration of actionaction

Please refer to the Mood Disorder, Please refer to the Mood Disorder, Psychosis, Anxiety Disorder and Psychosis, Anxiety Disorder and SubstanceSubstance--Related Disorder lectures for Related Disorder lectures for further discussions of medications forfurther discussions of medications forfurther discussions of medications for further discussions of medications for specific psychiatric diagnosesspecific psychiatric diagnoses

Also the webAlso the web--based cases have based cases have pharmacologic discussions that may be pharmacologic discussions that may be helpfulhelpful

Take home pointsTake home points

Be clear on the diagnosis you are treating Be clear on the diagnosis you are treating andand any comorbid diagnoses when you any comorbid diagnoses when you are selecting an agent to treatare selecting an agent to treat-- often can often can get 2 birds with 1 stone!get 2 birds with 1 stone!get 2 birds with 1 stone!get 2 birds with 1 stone!

Select the agent based on patients history, Select the agent based on patients history, current symptom profile and the side effect current symptom profile and the side effect profile of the medicationprofile of the medication-- there is no one there is no one correct answer in most cases.correct answer in most cases.

Monitor for efficacy and tolerance and Monitor for efficacy and tolerance and adjust as indicated. adjust as indicated.

If the patient does not improve step back, If the patient does not improve step back, rethink your diagnosis and treatment plan!rethink your diagnosis and treatment plan!rethink your diagnosis and treatment plan!rethink your diagnosis and treatment plan!

Keep an eye on drugKeep an eye on drug--drug interactionsdrug interactions