Pharmacological Treatments of Affective and Anxiety Disorders Flashcards
what are the indications for antidepressants?
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.
how do antidepressants work?
how do you select which antidepressant to use?
Antidepressant efficacy is similar so selection is based on past history of a response, side effect profile and coexisting medical conditions.
how long does it take for antidepressants to show an effect and what do you do if it doesnt show an effect?
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.
what are the different antidepressant classifications?
Tricyclics (TCAs)
Monoamine Oxidase Inhibitors (MAOIs)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Serotonin/Noradrenaline Reuptake Inhibitors (SNRIs)
Novel antidepressants
what are the features TCAs and what can it cause?
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
how do TCAs work?
work by increasing both serotonin, dopamine and noradrenaline
what are the 2 types of TCAs?
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
what are Monoamine Oxidase Inhibitors (MAOIs)?
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
what is the cheese reaction?
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
what is serotonin syndrome and what does it cause?
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
how do Selective Serotonin Reuptake Inhibitors (SSRIs)?
Block the presynaptic serotonin reuptake (so increase levels)
Treat both anxiety and depressive sx
what are the side effects of SSRIs?
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)
Discontinuation syndrome is more common with what drugs?
More common with shorter half life drugs so consider switching to fluoxetine (as longer half life).
whata re the symptoms of activation syndrome?
Activation Syndrome: Cause increased serotonin. Cab be distressing for patient
Nausea, increased anxiety, panic and agitation
whata re the pros and cons of Sertraline (SSRI)?
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
what are the pros of Fluoxetine (Prozac) - SSRI?
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
what are the cons of Fluoxetine (Prozac) - SSRI?
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
what are Serotonin/Norepinephrine reuptake inhibitors (SNRIs), how do they work and what are the used for?
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
what are the pros and cons of Venlafaxine (SNRI)?
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%
what are the pros and cons of Duloxetine (SNRI)?
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
what are the pros and cons of Novel antidepressants
Mirtazapine?
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)
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
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
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
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!!
what do you do if there is Treatment Resistance?
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!!
how is prophylaxis done?
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
what are the indications for Mood stabilizers? and what are the classes?
Indications: Bipolar, cyclothymia, schizoaffective, Classes: Lithium, anticonvulsants, antipsychotics
Which you select depends on what you are treating and again the side effect profile.
when is lithium used and what predicts a good response?
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)
how do you use lithium?
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
what are the side effects of lithium?
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
what are the different levels and effects of lithium toxicity?
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
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?
rapid cycling patients (females>males)
comorbid substance issues
mixed patients
Patients with comorbid anxiety disorders
how is Valproic acid used?
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
what are the side effects of valproic acid?
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
what is Carbamazepine (Tegretol)?
First line agent for acute mania and mania prophylaxis
Indicated for rapid cyclers and mixed patients
how do you use Carbamazepine (Tegretol)?
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
what are the Carbamazepine side effects?
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!
does Carbamazepine have drug interactions?
many
Lamotrigine ( Lamictal) - anticonvusalnt
how is it used?
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
whata re the side effects of Lamotrigine?
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
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?
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
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?
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
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?
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
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??
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
If patient refusing treatment orally use IM
Sedation plus the antipsychotic to treat the manic episode
how is prophylaxis used?
