Assistant Professor, University of Washington School of Medicine
I have no financial relationships to disclose relating to the subject matter of this presentation
Objectives: At the end of this session you should be able to:
Identify general pharmacologic strategies
Discuss antidepressants including indications for use and side effects
Describe mood stabilizers including indications for use and side effects
Review antipsychotics including how to choose an antipsychotic and side effects
Identify anxiolytic classes and indications for use
General Pharmacology strategies
Indication: Establish a diagnosis and identify the target symptoms that will be used to monitor therapy response.
Choice of agent and dosage: Select an agent with an acceptable side effect profile and use the lowest effective dose. Remember the delayed response for many psych meds and drug-drug interactions.
Establish informed consent: The patient should understand the benefits and risks of the medication. Make sure to document this discussion including pt understanding and agreement. In fertile women make sure to document teratogenicity discussion.
Implement a monitoring program: Track and document compliance, side effects, target symptom response, blood levels and blood tests as appropriate.
Management: Adjust dosage for optimum benefit, safety and compliance. Use adjunctive and combination therapies if needed however always strive for the simplest regimen. Keep your therapeutic endpoint in mind.
Indications: Unipolar and bipolar depression, organic mood disorders, schizoaffective disorder, anxiety disorders including OCD, panic, social phobia, PTSD, premenstrual dysphoric disorder and impulsivity associated with personality disorders.
General guidelines for antidepressant use
Antidepressant efficacy is similar so selection is based on past history of a response, side effect profile and coexisting medical conditions.
There is a delay typically of 3-6 weeks after a therapeutic dose is achieved before symptoms improve.
If no improvement is seen after a trial of adequate length (at least 2 months) and adequate dose, either switch to another antidepressant or augment with another agent.
Very effective but potentially unacceptable side effect profile i.e. antihistaminic, anticholinergic, antiadrenergic
Lethal in overdose (even a one week supply can be lethal!)
Can cause QT lengthening even at a therapeutic serum level
Have tertiary amine side chains
Side chains are prone to cross react with other types of receptors which leads to more side effects including antihistaminic (sedation and weight gain), anticholinergic (dry mouth, dry eyes, constipation, memory deficits and potentially delirium), antiadrenergic (orthostatic hypotension, sedation, sexual dysfunction)
Side effects are the same as tertiary TCAs but generally are less severe
Examples: Desipramine, notrtriptyline
Monoamine Oxidase Inhibitors (MAOIs)
Bind irreversibly to monoamine oxidase thereby preventing inactivation of biogenic amines such as norepinephrine, dopamine and serotonin leading to increased synaptic levels.
Are very effective for depression
Side effects include orthostatic hypotension, weight gain, dry mouth, sedation, sexual dysfunction and sleep disturbance
Hypertensive crisis can develop when MAOI’s are taken with tyramine-rich foods or sympathomimetics.
Serotonin Syndrome can develop if take MAOI with meds that increase serotonin or have sympathomimetic actions. Serotonin syndrome sx include abdominal pain, diarrhea, sweats, tachycardia, HTN, myoclonus, irritability, delirium. Can lead to hyperpyrexia, cardiovascular shock and death.
To avoid need to wait 2 weeks before switching from an SSRI to an MAOI. The exception of fluoxetine where need to wait 5 weeks because of long half-life.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Block the presynaptic serotonin reuptake
Treat both anxiety and depressive sx
Most common side effects include GI upset, sexual dysfunction (30%+!), anxiety, restlessness, nervousness, insomnia, fatigue or sedation, dizziness
Very little risk of cardiotoxicity in overdose
Can develop a discontinuation syndrome with agitation, nausea, disequilibrium and dysphoria
Short half life with no active metabolite means no build-up (which is good if hypomania develops)
Sedating properties (dose at night) offers good initial relief from anxiety and insomnia
Significant CYP2D6 inhibition
Sedating, wt gain, more anticholinergic effects
Likely to cause a discontinuation syndrome
Very weak P450 interactions (only slight CYP2D6)
Short half life with lower build-up of metabolites
Less sedating when compared to paroxetine
Max absorption requires a full stomach
Increased number of GI adverse drug reactions
Long half-life so decreased incidence of discontinuation syndromes. Good for pts with medication noncompliance issues
Initially activating so may provide increased energy
Secondary to long half life, can give one 20mg tab to taper someone off SSRI when trying to prevent SSRI Discontinuation Syndrome
Long half life and active metabolite may build up (e.g. not a good choice in patients with hepatic illness)
Significant P450 interactions so this may not be a good choice in pts already on a number of meds
Initial activation may increase anxiety and insomnia
More likely to induce mania than some of the other SSRIs
Low inhibition of P450 enzymes so fewer drug-drug interactions
Intermediate ½ life
Dose-dependent QT interval prolongation with doses of 10-30mg daily- due to this risk doses of >40mg/day not recommended!
Can be sedating (has mild antagonism at H1 histamine receptor)
GI side effects (less than sertraline)
Low overall inhibition of P450s enzymes so fewer drug-drug interactions
Intermediate 1/2 life
More effective than Citalopram in acute response and remission
Dose-dependent QT interval prolongation with doses of 10-30mg daily
Increases serum cholesterol by 20% in 15% of patients and triglycerides in 6% of patients
Very sedating at lower doses. At doses 30mg and above it can become activating and require change of administration time to the morning.
Associated with weight gain (particularly at doses below 45mg
Good for use as an augmenting agent
Mechanism of action likely reuptake inhibition of dopamine and norepinephrine
No weight gain, sexual side effects, sedation or cardiac interactions
Low induction of mania
Is a second line ADHD agent so consider if patient has a co-occurring diagnosis
May increase seizure risk at high doses (450mg+) and should avoid in patients with Traumatic Brain Injury, bulimia and anorexia.
Does not treat anxiety unlike many other antidepressants and can actually cause anxiety, agitation and insomnia
Has abuse potential because can induce psychotic sx at high doses
Susie Q has a nonpsychotic unipolar depression with no history of hypomania or mania. She has depressed mood, hyperphagia, psychomotor retardation and hypersomnolence. What agent would you like to use for her?
Establish dx: Major depressive disorder
Target symptoms: depression, hyperphagia, psychomotor retardation and hypersomnolence
For a treatment naive patient start with an SSRI.
Using the side effect profile as a guide select an SSRI that is less sedating. Good choices would be Citalopram, Fluoxetine or Sertraline. Buproprion would also have been a reasonable choice given her hypersomnolence, psychomotor retardation and hyperphagia.
Less desirable choices include Paxil and Mirtazapine because of sedation and wt gain.
Not a duel reuptake inhibitors because she is treatment naïve and may not need a “big gun”.
Not a TCA because of side effects
Billy bob is a 55 year old diabetic man with mild HTN and painful diabetic neuropathy who has had previous depressive episodes and one suicide attempt. He meets criteria currently for a major depressive episode with some anxiety. He has been treated with paroxetine, setraline and buproprion. His depression was improved slightly with each of these meds but never remitted. What would you like to treat him with?
Case 2 continued
Establish dx: Major depressive disorder with anxious features
Target symptoms: depressive sx, anxiety and possibly his neuropathic pain
Assuming he received adequate trials previously would move on to a duel reuptake inhibitor as he had not achieved remission with two SSRIS or a novel agent.
Case 2 continued
Given his mild HTN would not choose Venlafaxine. TCA’s can help with neuropathic pain and depression however not a good choice given the SE profile and lethality in overdose. Duloxetine is a good choice since it has an indication for neuropathic pain, depression and anxiety. Three birds with one stone!!
Keep in mind Duloxetine is a CYP2D6 and CPY1A2 inhibitor and has potential drug-drug interactions.
Indications: Bipolar, cyclothymia, schizoaffective, impulse control and intermittent explosive disorders.
Classes: Lithium, anticonvulsants, antipsychotics
Which you select depends on what you are treating and again the side effect profile.
Only medication to reduce suicide rate.
Rate of completed suicide in BAD ~15%
Effective in long-term prophylaxis of both mania and depressive episodes in 70+% of BAD I pts
Before starting :Get baseline creatinine, TSH and CBC. In women check a pregnancy test- during the first trimester is associated with Ebstein’s anomaly 1/1000 (20X greater risk than the general population)
Monitoring: Steady state achieved after 5 days- check 12 hours after last dose. Once stable check q 3 months and TSH and creatinine q 6 months.
Goal: blood level between 0.6-1.2
Lithium side effects
Most common are GI distress including reduced appetite, nausea/vomiting, diarrhea
Polyuria/polydypsia secondary to ADH antagonism. In a small number of patients can cause interstitial renal fibrosis.
First line agent for acute mania and mania prophylaxis
Indicated for rapid cyclers and mixed patients
Before med is started: baseline liver function tests, CBC and an EKG
Monitoring: Steady state achieved after 5 days -check 12 hours after last dose and repeat CBC and lfts
Goal: Target levels 4-12mcg/ml
Need to check level and adjust dosing after around a month because induces own metabolism.
Carbamazepine side effects
Rash- most common SE seen
Nausea, vomiting, diarrhea, transaminitis
Sedation, dizziness, ataxia, confusion
AV conduction delays
Aplastic anemia and agranulocytosis (<0.002%)
Water retention due to vasopressin-like effect which can result in hyponatremia
Drugs that increase carbamazepine levels and/or toxicity: acetazolamide, cimetidine (both can cause rapid toxic reactions), clozapine (may act synergistically to suppress BM), diltiazem, INH, fluvoxamine, occasionally fluoxetine, erythromycin, clarithromycin, fluconazole, itraconazole, ketoconazole, metronidazole, propoxyphene, verapamil, diltiazem.
Drugs that decrease carbamazepine levels: neuroleptics, barbiturates, phenytoin, TCA’s.
VPA may increase or decrease carbamazepine levels.
Carbamazepine is a heteroinducer, increasing its own metabolism and that of many other drugs, including estrogen and progesterone (contraceptives), warfarin, methadone, many psychotropics including antidepressants, antipsychotics, BZD’s, in addition to cyclosporine (and other immunosuppressants), theophylline, etc.
Initiation/titration: start with 25 mg daily X 2 weeks then increase to 50mg X 2 weeks then increase to 100mg- faster titration has a higher incidence of serious rash
If the patient stops the med for 5 days or more have to start at 25mg again!
Lamotrigine: Side effects
Sedation, dizziness, ataxia and confusion
The most severe are toxic epidermal necrolysis and Stevens Johnson's Syndrome. The character/severity of the rash is not a good predictor of severity of reaction. Therefore, if ANY rash develops, discontinue use immediately.
Blood dyscrasias have been seen in rare cases.
Drugs that increase lamotrigine levels: VPA (doubles concentration, so use slower dose titration), sertraline.
Antipsychotics as mood stabilizers
Olanzapine fluoxetine comb
FDA approved indications in Bipolar disorder
*denotes FDA approval for adjunct therapy not mono-therapy
33 yo woman hospitalized with her first episode of mania. She has no previous history of a depressive episode. She has no drug or ETOH history and has no medical issues. What medication would you like to start?
Given her first presentation was a manic episode statistically she will do better on lithium.
Make sure to check a pregnancy test, serum creatinine and TSH prior to initiation of treatment.
Discuss with her what she will use for birth control and document this discussion.
You start her at 300mg BID (average starting dose) and when she comes to see you in one week she is complaining about stomach irritation and some diarrhea. What do you think is going on and what should you do?
GI irritation including diarrhea is common particularly early in treatment. Encourage pt to drink adequate fluid, leave at current dose and see if side effects resolve.
27 yo male is admitted secondary to a manic episode. In reviewing his history you find he has 5 to 6 manic or depressive episodes a year. He has also struggled on and off with ETOH abuse. What medication would you like to start?
Depakote would be a good choice because pt is a rapid cycler (4 or more depressive or manic episodes/year) and because of comorbid ETOH abuse.
You start 250mg BID and titrate to 500mg BID. His depakote level is 70. You check his lfts and compared to baseline they have increased as follows:
ALT 48 115
ALK PHOS 3280
What happened and what do you want to do??
It is not unusual for patients on anticonvulsants to experience an increase in lfts and as long as they do not more than triple no change in therapy is indicated.
Continue to monitor over time
Indications for use: schizophrenia, schizoaffective disorder, bipolar disorder- for mood stabilization and/or when psychotic features are present, delirium, psychotic depression, dementia, trichotillomania, augmenting agent in treatment resistant anxiety disorders.
Key pathways affected by dopamine in the Brain
MESOCORTICAL- projects from the ventral tegmentum (brain stem) to the cerebral cortex. This pathway is felt to be where the negative symptoms and cognitive disorders (lack of executive function) arise. Problem here for a psychotic patient, is too little dopamine.
MESOLIMBIC-projects from the dopaminergic cell bodies in the ventral tegmentum to the limbic system. This pathway is where the positive symptoms come from (hallucinations, delusions, and thought disorders). Problem here in a psychotic patient is there is too much dopamine.
NIGROSTRIATAL- projects from the dopaminergic cell bodies in the substantia nigra to the basal ganglia. This pathway is involved in movement regulation. Remember that dopamine suppresses acetylcholine activity. Dopamine hypoactivity can cause Parkinsonian movements i.e. rigidity, bradykinesia, tremors), akathisia and dystonia.
TUBEROINFUNDIBULAR-projects from the hypothalamus to the anterior pituitary. Remember that dopamine release inhibits/regulates prolactin release. Blocking dopamine in this pathway will predispose your patient to hyperprolactinemia (gynecomastia/galactorrhea/decreased libido/menstrual dysfunction).
Are D2 dopamine receptor antagonists
High potency typical antipsychotics bind to the D2 receptor with high affinity. As a result they have higher risk of extrapyramidal side effects. Examples include Fluphenazine, Haloperidol, Pimozide.
Low potency typical antipsychotics have less affinity for the D2 receptors but tend to interact with nondopaminergic receptors resulting in more cardiotoxic and anticholinergic adverse effects including sedation, hypotension. Examples include chlorpromazine and Thioridazine.
The Atypical Antipsychotics - atypical agents are serotonin-dopamine 2 antagonists (SDAs)
They are considered atypical in the way they affect dopamine and serotonin neurotransmission in the four key dopamine pathways in the brain.
Functions more like a typical antipsychotic at doses greater than 6mg
Increased extrapyramidal side effects (dose dependent)
Most likely atypical to induce hyperprolactinemia
Weight gain and sedation (dosage dependent)
Available in regular tabs, immediate release IM, rapidly dissolving tab, depo form
Weight gain (can be as much as 30-50lbs with even short term use)
May cause hypertriglyceridemia, hypercholesterolemia, hyperglycemia (even without weight gain)
May cause hyperprolactinemia (< risperidone)
May cause transaminitis (2% of all patients)
Available in a regular tablet form only
May cause transaminitis (6% of all patients)
May be associated with weight gain, though less than seen with olanzapine
May cause hypertriglyceridemia, hypercholesterolemia, hyperglycemia (even without weight gain), however less than olanzapine
Most likely to cause orthostatic hypotension
Available regular tabs and IM immediate release form
Clinically significant QT prolongation in susceptible patients
May cause hyperprolactinemia (< risperidone)
No associated weight gain
Absorption is increased (up to 100%) with food
Available in regular tabs, immediate release IM formulation and depo form
Unique mechanism of action as a D2 partial agonist
Low EPS, no QT prolongation, low sedation
CYP2D6 (fluoxetine and paroxetine), 3A4 (carbamazepine and ketoconazole) interactions that the manufacturer recommends adjusted dosing. Could cause potential intolerability due to akathisia/activation.
Not associated with weight gain
Available in 1 form- a regular tablet
Is reserved for treatment resistant patients because of side effect profile but this stuff works!
Associated with agranulocytosis (0.5-2%) and therefore requires weekly blood draws x 6 months, then Q- 2weeks x 6 months)
Increased risk of seizures (especially if lithium is also on board)
Associated with the most sedation, weight gain and transaminitis
Increased risk of hypertriglyceridemia, hypercholesterolemia, hyperglycemia, including nonketotic hyperosmolar coma and death with and/or without weight gain
Comes in regular tabs
Needs BID dosing
Titrate over 4 daysto 12mg/day in order to minimize risk of orthostatic hypotension
Inhibitors of 3A4 (ketoconazole) or 2D6 (fluoxetine, paroxetine)-Can increase blood levels two-fold!
QT Prolongation- mean increase of 19msec at 12mg BID
Not recommended for patients with hepatic impairment
Citrome L, Postgraduate Medicine 2011
Sublingual (no food or liquid for 10 min)
BID dosing required
Can start at therapeutic dose
Low wt gain and metabolic disturbances
Sedation, somnolence, akathisia
Not recommended for patients with severe hepatic impairment
Be careful with co-administration of (CYP1A2 inhibitor)
Can dose once daily and start at therapeutic dose
No QT prolongation warning
Less treatment emergent weight gain and metabolic disturbances
Must administer with food (>350kcals)
Is associated with akathisia, sedation
Dose should not exceed 40mg day in patients with moderate to severe renal or hepatic impairment
Contraindicated co-administration with CYP 3A4 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 effects
Tardive Dyskinesia (TD)-involuntary muscle movements that may not resolve with drug discontinuation- risk approx. 5% per year
Neuroleptic Malignant Syndrome (NMS): Characterized by severe muscle rigidity, fever, altered mental status, autonomic instability, elevated WBC, CPK and lfts. Potentially fatal.
Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome, Akathisia
Agents for EPS
Anticholinergics such as benztropine, trihexyphenidyl, diphenhydramine
Dopamine facilitators such as Amantadine
Beta-blockers such as propranolol
Need to watch for anticholinergic SE particularly if taken with other meds with anticholinergic activity ie TCAs
21 yo AA male with symptoms consistent with schizophrenia is admitted because of profound psychotic sx. He is treatment naïve. You plan to start an antipsychotic- what baseline blood work would you obtain?
Many atypical antipsychotics can cause dyslipidemia, transaminitis and elevated blood sugars and there is a class risk of diabetes unrelated to weight gain so you need the following:
Fasting lipid profile
Fasting blood sugar
His labs come back as follows:
Total Cholesterol:215 HDL:30 LDL:145
Lfts, CBC WNL
What agent would you like to start?
Pt has mildly elevated total cholesterol and a low HDL for his age. Would not choose Olanzapine or Quetiapine given risk of dyslipidemia. Risperidone, Ziprasidone or Aripiprazole are good choices.
You start Risperidone and titrate to 3mg BID (high average dose). He starts to complain that he “feels uncomfortable in my skin like I can’t sit still”. What is likely going on and what are you going to do about it?
He is likely experiencing akathisia. This is not uncommon with Risperidone. Given he was very ill reducing the dose may not be the best choice so likely treat with an anticholinergic agent or propranolol. You need to treat akathisia because it is associated with an increase risk for suicide!
Used to treat many diagnoses including panic disorder, generalized Anxiety disorder, substance-related disorders and their withdrawal, insomnias and parasomnias. In anxiety disorders often use anxiolytics in combination with SSRIS or SNRIs for treatment.
Good augmentation strategy- Mechanism of action is 5HT1A agonist. It works independent of endogenous release of serotonin.
Takes around 2 weeks before patients notice results.
Will not reduce anxiety in patients that are used to taking BZDs because there is no sedation effect to “take the edge off.
Used to treat insomnia, parasomnias and anxiety disorders.
Often used for CNS depressant withdrawal protocols ex. ETOH withdrawal.
Dose Equivalency (mg)
Peak Blood Level (hours)
Elimination Half- Life1 (hours)
Rapid oral absorption
Active metabolites; erratic bioavailability from IM injection
Can have layering effect
Active metabolites; erratic bioavailability from IM injection
Active metabolites with long half-lives
No active metabolites
No active metabolites
Slow oral absorption
Rapid onset; short duration of action
Please refer to the Mood Disorder, Psychosis, Anxiety Disorder and Substance-Related Disorder lectures for further discussions of medications for specific psychiatric diagnoses
Also the web-based cases have pharmacologic discussions that may be helpful
Take home points
Be clear on the diagnosis you are treating and any comorbid diagnoses when you are selecting an agent to treat- often can get 2 birds with 1 stone!
Select the agent based on patients history, current symptom profile and the side effect profile of the medication- there is no one correct answer in most cases.
Monitor for efficacy and tolerance and adjust as indicated.
If the patient does not improve step back, rethink your diagnosis and treatment plan!