Pharmacological Treatments of Affective and Anxiety Disorders

Question 1

what are the indications for antidepressants?

Answer 1

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.

Question 2

how do antidepressants work?

Answer 2

Question 3

how do you select which antidepressant to use?

Answer 3

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

Question 4

how long does it take for antidepressants to show an effect and what do you do if it doesnt show an effect?

Answer 4

There is a delay typically of 2-4 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.

Question 5

what are the different antidepressant classifications?

Answer 5

Tricyclics (TCAs)

Monoamine Oxidase Inhibitors (MAOIs)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin/Noradrenaline Reuptake Inhibitors (SNRIs)

Novel antidepressants

Question 6

what are the features TCAs and what can it cause?

Answer 6

Very effective but potentially unacceptable side effect profile i.e. antihistaminic (weight gain, sleepy), anticholinergic, antiadrenergic (dry mouth, blurred vision)

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

Can cause QT lengthening even at a therapeutic serum level

Question 7

how do TCAs work?

Answer 7

work by increasing both serotonin, dopamine and noradrenaline

Question 8

what are the 2 types of TCAs?

Answer 8

Tertiary TCAs - Have tertiary amine side chains, Side chains are prone to cross react with other types of receptors which leads to more side effects

Secondary TCAs - Are often metabolites of tertiary amines, Primarily block noradrenaline, Side effects are the same as tertiary TCAs but generally are less severe

Question 9

what are Monoamine Oxidase Inhibitors (MAOIs)?

Answer 9

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

Are very effective for resistant depression

Side effects include orthostatic hypotension, weight gain, dry mouth, sedation, sexual dysfunction and sleep disturbance

Question 10

what is the cheese reaction?

Answer 10

Hypertensive crisis can develop when MAOI’s are taken with tyramine-rich foods or sympathomimetics. *Cheese Reaction!!

Cheese

Red wine

Some processed meats

Strict diet

Question 11

what is serotonin syndrome and what does it cause?

Answer 11

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

Question 12

how do Selective Serotonin Reuptake Inhibitors (SSRIs)?

Answer 12

Block the presynaptic serotonin reuptake (so increase levels)

Treat both anxiety and depressive sx

Question 13

what are the side effects of SSRIs?

Answer 13

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 (when you stop them quickly)

Question 14

Discontinuation syndrome is more common with what drugs?

Answer 14

More common with shorter half life drugs so consider switching to fluoxetine (as longer half life).

Question 15

whata re the symptoms of activation syndrome?

Answer 15

Activation Syndrome: Cause increased serotonin. Cab be distressing for patient

Nausea, increased anxiety, panic and agitation

Question 16

whata re the pros and cons of Sertraline (SSRI)?

Answer 16

Pros”

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

Cons:

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

Question 17

what are the pros of Fluoxetine (Prozac) - SSRI?

Answer 17

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

Question 18

what are the cons of Fluoxetine (Prozac) - SSRI?

Answer 18

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

Question 19

what are Serotonin/Norepinephrine reuptake inhibitors (SNRIs), how do they work and what are the used for?

Answer 19

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

Used for depression, anxiety and possibly neuropathic pain

Go-to med if someone hasn’t response to SSRI

Question 20

what are the pros and cons of Venlafaxine (SNRI)?

Answer 20

Pros:

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

Cons:

• Can cause a 10-15 mmHG dose dependent increase in diastolic BP
• May cause significant nausea, primarily with immediate-release (IR) tabs
• Can cause a bad discontinuation syndrome, and taper recommended after 2 weeks of administration
• Noted to cause QT prolongation
• Sexual side effects in >30%

Question 21

what are the pros and cons of Duloxetine (SNRI)?

Answer 21

Pros:

• Some data to suggest efficacy for the physical symptoms of depression
• Thus far less BP increase as compared to venlafaxine, however this may change in time

Cons:

• CYP2D6 and CYP1A2 inhibitor
• Cannot break capsule, as active ingredient not stable within the stomach
• In pooled analysis had higher drop out rate

Question 22

what are the pros and cons of Novel antidepressants
Mirtazapine?

Answer 22

Pros:

• Different mechanism of action may provide a good augmentation strategy to SSRIs (Effects different serotonin receptors to SSRIs). Is a 5HT2 and 5HT3 receptor antagonist
• Can be utilized as a hypnotic at lower doses secondary to antihistaminic effects

Cons:

• 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)

Question 23

Case 1:

Susie 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

Answer 23

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

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

Not a duel reuptake inhibitors because she is treatment naïve

Not a TCA because of side effects

Question 24

Case 2:

ob is a 55 year old diabetic man with mild HTN (hypertension) 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, sertraline and mirtazepine. His depression was improved slightly with each of these meds but never remitted. What would you like to treat him with?

Establish dx: Major depressive disorder with anxious features

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

Answer 24

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

SNRI = dual

Given his mild HT 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!!

Question 25

what do you do if there is Treatment Resistance?

Answer 25

First go to would be Combination of antidepressants eg SSRI or SNRI with Mirtazepine

Adjunctive treatment with Lithium (Lithium has shown to be a good adjunctive therapy for antidepressive therapy)

Adjunctive treatment with atypical antipsychotic eg Quetipaine, Olanzapine or Aripiprazole

ECT!!

Question 26

how is prophylaxis done?

Answer 26

First episode continue for 6mth to a year

Second episode continue for 2 years

Third episode disucuss life long

stop before 6 months 80% relapse

Prophylaxis > 6 months 20% relapse

Question 27

what are the indications for Mood stabilizers? and what are the classes?

Answer 27

Indications: Bipolar, cyclothymia, schizoaffective, Classes: Lithium, anticonvulsants, antipsychotics

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

Question 28

when is lithium used and what predicts a good response?

Answer 28

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

Factors predicting positive response to lithium:

• Prior long-term response or family member with good response
• Classic pure mania
• Mania is followed by depression

(BAD = bipolar affective disorder)

Question 29

how do you use lithium?

Answer 29

Before starting: Get baseline U&E and TSH (Need to get baseline blood as affects renal function and thyroid). 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 level 3 months and TSH and creatinine 6 months

Goal: blood level between 0.6-1.2

Question 30

what are the side effects of lithium?

Answer 30

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

Thyroid abnormalities

Nonsignificant leukocytosis

Polyuria/polydypsia secondary to ADH antagonism. In a small number of patients can cause interstitial renal fibrosis. (can lead to renal failure in long term use)

Hair loss, acne

Reduces seizure threshold, cognitive slowing, intention tremor

Question 31

what are the different levels and effects of lithium toxicity?

Answer 31

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

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

Severe- >2.5 generalized convulsions, oliguria and renal failure

Question 32

Anticonvulsant - Valproic acid (Depakote)

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

Better tolerated than Lithium

Not as good for depressive side of things

Factors predicting a positive response - what are they?

Answer 32

rapid cycling patients (females>males)

comorbid substance issues

mixed patients

Patients with comorbid anxiety disorders

Question 33

how is Valproic acid used?

Answer 33

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

Avoid in woman of child bearing age due to neural tube defects

Monitoring: Steady state achieved after 4-5 days -check 12 hours after last dose and repeat CBC (blood count) and lfts

Goal: target level is between 50-125

Question 34

what are the side effects of valproic acid?

Answer 34

Thrombocytopenia and platelet dysfunction

Nausea, vomiting, weight gain (these 3 are most common)

Sedation, tremor

Increased risk of neural tube defect 1-2% vs 0.14-0.2% in general population secondary to reduction in folic acid

Hair loss

Question 35

what is Carbamazepine (Tegretol)?

Answer 35

First line agent for acute mania and mania prophylaxis

Indicated for rapid cyclers and mixed patients

Question 36

how do you use Carbamazepine (Tegretol)?

Answer 36

Before med is started: baseline liver function tests, FBC and an ECG

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

Much more based on response compared to lithium

Question 37

what are the Carbamazepine side effects?

Answer 37

Rash - most common SE seen

Nausea, vomiting, diarrhea

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

Drug-drug interactions!

Question 38

does Carbamazepine have drug interactions?

Answer 38

many

Question 39

Lamotrigine ( Lamictal) - anticonvusalnt

how is it used?

Answer 39

Indications similar to other anticonvulsants. Also used for neuropathic/chronic pain

Before med is started: baseline liver function tests

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!

No problem with child bearing age

Question 40

whata re the side effects of Lamotrigine?

Answer 40

Nausea/vomiting

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

Question 41

Case 3:

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 (alcohol) history and has no medical issues. What medication would you like to start?

Answer 41

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

Question 42

Case 3 continued:

You start her at 800mg nocte (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?

Answer 42

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

Question 43

Case 4:

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 (alcohol) abuse. What medication would you like to start?

Answer 43

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 (alcohol) abuse

No concern of neural tube defects as he is male

Question 44

Case 4 continued:

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

• ALT 48 - 115
• AST 62 - 140
• ALK PHOS 32 - 80

Everything has gone up

What happened and what do you want to do??

Answer 44

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

Question 45

Answer 45

If patient refusing treatment orally use IM

Sedation plus the antipsychotic to treat the manic episode

Question 46

how is prophylaxis used?

Answer 46