Antipsychotics and Bipolar Disorder Flashcards
What is schizophrenia?
Chronic psychosis with deterioration of functional capacity. The inability to interact mentally and emotionally with other people.
When are the onsets for schizophrenia for the different genders?
Males are more at risk than females
Males: 15-24 years
Females: 25-34 years
Genetic predisposition, not fatal
What are the positive symptoms of schizophrenia?
Excess cognition
Hallucinations (false sensory perceptions), delusions (fixed false beliefs), disorganized speech
What are the negative symptoms of schizophrenia?
Deficits in behaviour
Avolition (lack of desire or motivation), Alogia (poverty of speech), Anhedonia (lack of pleasure in completing tasks that were once pleasurable) and blunted affect (flat mood).
What are the cognitive symptoms of schizophrenia?
Declines in attention, language, memory and executive function
Probably present from birth
What are the affective symptoms of schizophrenia?
Blunted, inappropriate, odd expression
Often lead to social stigmatization
What is the dopamine hypothesis of schizophrenia?
Too much mesolimbic dopamine pathway activity to the nucleus accumbens leads to positive symptoms
Low dopaminergic activity in the mesocortical pathway to the prefrontal cortex leads to neagtive symptoms
All dopamine signals come from the ventral tegmental area
What is the nucleus accumbens responsible for?
Motivation, reward, addiction and reinforcing behaviour
What is the prefrontal cortex responsible for?
Cognition, communication, social function and stress response
How is the dopamine hypothesis supported?
Most antipsychotics strongly block D2 dopamine receptors
Drugs that increase dopaminergic activity can produce psychosis
How doe typical antipsychotics work?
Antagonism of the D2 receptors in the mesolimbic pathway, providing effective relief from positive symptoms
What are some examples of typical antipsychotics (FGAs)?
Chlorpromazine, Fluphenazine, Haloperidol, Thiothixene
What are the adverse effects of typical antipsychotics related to?
Receptor non-selectivity
Blockade of non-mesolimbic D2 dopaminergic pathways
What are some of the adverse effects of typical antipsychotics that come from the antimuscarinic effects?
Toxic confusional state, dry mouth, urinary retention
What are some of the adverse effects of typical antipsychotics that come from the alpha 1 adrenergic block?
Orthostatic hypotension, dizziness, tachycardia, impotence
What are some of the adverse effects of typical antipsychotics that come from the histamine H1 blockade?
Weight gain, sedation
What is the nigrostriatal pathway?
The substantia niagra sends D2 dopamine signals to the striatum which controls coordination and voluntary movement
What happens when there is D2 blockade in the nigrostriatal pathway?
Extrapyramidal side effects (EPS): Parkinson’s syndrome, Akathisia (slowed movements), Acute dystonic reactions (abnormal muscle spasm), Tardive dyskinesia (unusual movement, blinking, jerking-can be irreversible, no reliable treatment)
What is the tuberoinfundibular pathway?
The hypothalamus sends D2 dopamine signals to the pituitary gland, which controls prolactin secretion (keeps it low)
What happens when there is D2 blockade in the tuberoinfundibular pathway?
Increased prolactin production causing lactation, amenrrohea and infertility in women
Lactation, impotence, decreased libido and gynecomastia in men
What are some other adverse effects of typical antipsychotics?
Pseudodepression, corneal and lens deposits (chlorpromazine), retinal deposits and cardiac arrhythmias in overdose (thioridizine)
Neuroleptic malignant syndrome (severe muscle rigidity, impaired sweating, fever, severe agitation)
What are the advantages of atypical antipsychotics?
Block D2 receptors in the nucleus accumbens to decrease positive symptoms
Decreased D2 affinity in the nigrostriatal pathway to decrease extrapyramidal side effects
Blocks 5-HT2 receptors (serotonin-usually stops dopamine) to decrease negative symptoms by increase mesocortical dopamine
What are some examples of atypical antipsychotics?
Resperidone, Olanzapine, Quetiapine, Ziprasidone, Clozapine (D4 receptors, not D2), Aripiprazole (D2 partial agonist, serotonin agonist)
What are the adverse effects of atypical antipsychotics?
Generally the same side effects as typical antipsychotics but with a lower risk, especially of EPS
Seizures and agranulocytosis (clozapine), weight gain, hyperlipidemia, hyperglycemia, type 2 diabetes (clozapine, olanzapine)
Higher death rate in the elderly with dementia
What are the CYP 3A4 drug interactions with atypical antipsychotics?
Clozapine, Quetiapine, Aripiprazole will be decreased by Fluoxetine and Grapefruit juice
Will be increased by St. John’s wort
What about atypical antipsychotics causes weight gain?
H1 blockade
What are the CYP 1A2 drug interactions with antipsychotics?
Clozapine, Olanzapine, Typical antipsychotics will be decreased by ciprofloxacin
Increased by smoking
What are the CYP 2D6 drug interactions with antipsychotics?
Risperidone, Phenothiazine, Typical antipsychotics will be decreased by paroxetine
Which drugs will interact and cause excess sedation with antipsychotics?
Anxiolytics, alcohol, antidepressants, antihistamines
Which drugs will interact and cause additive antimuscarinic effects with antipsychotics?
Antimuscarinics
What does metoclopramide do when it interacts with antipsychotics?
It is a D2 antagonist so it causes extrapyramidal symptoms
What do SSRI antidepressants do when they interact with antipsychotics?
Increase serotonin, thus increase dopamine supression in the NGS and EPS
What is mania?
A distinct period of dramatically elevated, irritable mood lasting 1 week or more and impairing social functioning
What are some symptoms of mania?
Inflated self-esteem, reduced need for sleep, verbosity, racing thoughts, distractibility and risky behaviour
What is hypomania?
A briefer duration of manic symptoms. Will be less severe
What are the 2 subtypes of bipolar disorder?
Bipolar I: Episodes of sustained mania, usually with intervening depressive episodes
Bipolar II: Major depressive episodes with at least 1 manic episode
How does the prevalence of bipolar disorder differ between the two genders?
Bipolar I: Equal rates in males and females, onset is about 21
Bipolar II: More prevalent in females
What causes bipolar disorder?
Multiple defects, no solid grasp on the mechanism
What are some non-pharmacological treatments of bipolar disorder?
Adjust sleep, nutrition, exercise and stress levels
What are the pharmacological treatment options for bipolar disorder?
Mood stabilizers, atypical antipsychotics, adjunct therapy with benzodiazepines
What are some examples of mood stabilizers?
Lithium, valproate, lamogitrine, carbamazepine
What is the major working hypothesis behind the action of lithium?
Lithium affects the IP3/DAG second messenger system by blocking inositol recycling
What is lithium used for in bipolar disorder?
For manic phase and maintenance
Reduces risk of suicide
Slow onset and better drugs have reduced use
What is often given with lithium?
Patients with mania possessing psychotic features often recieve adjunct SGA (olanzapine)
What are the early adverse effects of lithium?
Nausea, vomiting, diarrhea, muscle weakness, polydipsia with polyuria/nocturia, headache, tremor, nephrogenic diabetes insipidus
What are the long-term adverse effects of lithium?
Renal morphology change, hypothyroidism, weight gain (>10 kg), reduced libido, edema, severe acne, cardiovascular
What are some of the problems with lithium?
Low therapeutic index, problematic in renal insufficiency
Which drugs interact to increase lithium?
Thiazide diuretics, NSAIDs, ACE inhibitors, Loop diuretics, Ca channel blockers
Which drugs interact to decrease lithium?
K-sparing diuretics, Loop diuretics, Ca channel blockers
What is carbamazepine used for in bipolar disorder?
Manic, depression and maintenance
Better for rapid cycling
What are the adverse effects of carbamazepine?
Nausea, vomiting, diarrhea, hyponatremia, rash, leukopenia, fluid retention, drowsiness, dizziness, lethargy and headache
What is valproate used for in bipolar disorder?
Manic
Patients not responsive to lithium, better for rapid cycling
What are the adverse effects of valproate?
Generally well-tolerated
But with increased doses, nausea, weight gain, diarrhea, vomiting, hair loss, tremor
How are antipsychotics used in the treatment of bipolar disorder?
Used alone or with mood stabilizers
How are benzodiazepines used in the treatment of bipolar disorder?
Clonazepam used with a mood stabilzers
Limited by abuse potential if more than acute
What drugs are used for the control of depressive episodes of bipolar disorder?
Lithium, lamotrigine, antipsychotics, antidepressants
Why is lamogitrine used as an alternative to lithium for maintenance?
Weight neutral
What antipsychotics are used for bipolar depression?
Olanzapine and fluoxetine
How should antidepressants be used in the treatment of bipolar disorder?
Monotherapy may increase cycling between mania and depression
No advantage of monotherapy or combination therapy (with a mood stabilizer)
Which drugs are used for maintenance therapy of bipolar disorder?
Lithium, Lamogitrine, Valproate, Carbemazepine
And psychotherapy
What defines lifetime bipolar disorder?
3 or more manic episodes or 1 moderate to severe manic episode
What is depression often comorbid with?
Anxiety
What is reactive (secondary) depression? How is it treated?
A temporary reaction to real stimuli (grief, illness)
Treated mostly by psychotherapy
What is major diepression?
One or more major depressive episodes free of manic, mixed or hypomanic episodes
Who is major depression more common in? When is the onset?
More common in females, genetic component
Onset is typically 25-44 years old
What are some emotional symptoms of major depression?
Persistent diminished ability to experience pleasure, loss of interest in usual activities, pessimistic outlook, anxiety
What are some physical symptoms of major depression?
Chronic fatigue, terminal insomnia, appetite disturbances
What are the cognitive symptoms of major depression?
Poor concentration, slow thinking, poor short-term memory, confusion
What are the psychomotor symptoms of major depression?
Slowed physical movements and speech, agitation
What are the non-pharmacologic treatment options for major depression?
Psychotherapy, electroconductive therapy (patient preference)
What is the amine hypothesis?
That depression is related to the reduced ability of the synapse to release norepinephrine and serotonin
How do most antidepressant drugs work?
Enhance synaptic monoamines by blocking normal neurotransmitter reuptake (not that simple based on therapeutic lag)
Long term effects on synaptic strength (presynaptic autoreceptor downregulation)
What is the therapeutic lag for antidepressants?
The drugs increase the neurotransmitter levels right away but efficacy is delayed 1-4 weeks.
What occurs in phase 1 of amine enhancement?
Short term (minutes to hours) uptake inhibition causing homeostatic agonist downregulation of the presynaptic receptors to maintain normal agonist:receptor interaction levels, resulting in reduced negative feedback and the phase 2 amine increase
What occurs in phase 2 of amine enhancement?
Long term (weeks) effects of the phase 1 enhancement which produces further enhanced amine levels to reach therapeutic signifigance
What normally happens in the synapse?
Pre-synaptic receptors that feedback inhibit to stop amine release.
What are some examples of tricyclic antidepressants?
Amitriptyline, imipramine, clomipramine
How do tricyclic antidepressants work?
Mixed norepinephrine and serotonin reuptake inhibitors, great variation in the each blockade potencies
Also some blockade of cholinergic, histaminergic, alpha 1 adrenergic receptors which give the adverse effects
What are TCAs also used for?
Neuropathic pain
What are some adverse effects of TCAs?
Sedation,
tremor, insomnia, (increased NE)
seizures, weight gain, sexual disturbances, cardiac arrythmias (overdose)
What are the drug interactions with TCAs?
CYP 2D6 inhibitors, highly protein bound (can displace other protein bound drugs)
Sedatives, sympathomimetics, antimuscarinics
What are some examples of serotonin selective reuptake inhibitors (SSRIs)?
Fluoxetine (most drug interactions), Paroxetine, Sertraline (least)
How do SSRIs work?
Block serotonin reuptake, not NE as much
Drug interactions differ between them
What are some adverse effects of SSRIs?
Mild, short-lived GI symptoms, headache, sexual dysfunction, fatigue, insomnia, platelet aggregation inhibition
Safer in overdose
Why do SSRIs have less side effects than TCAs?
Much less cholinergic, histaminergic, adrenergic receptor blockade than TCAs
What are some symptoms of paroxetine withdrawal?
Short half life=higher chance of physical dependence and withdrawal
Dizziness, nausea, tremor, anxiety
What are some drug interactions with SSRIs?
Strong CYP 2D6 inhibitors, TCAs, antipsychotics, beta-blockers, low non-SERT interactions
What are the advantages of using an SSRI over a TCA?
Equal efficacy with milder side effects, more favourable therapeutic index, smaller chance of additive drug interactions (anticholinergics)
What are some examples of SNRIs?
Venlafaxine
How do SNRIs work?
Inhibit both serotonin and norepinephrine reuptake (serotonin>NE)
Also weak dopamine reuptake inhibitor
No affinity for muscarinic, alpha 1 or histaminergic, may be useful for depression in conjunction with neuropathic pain
What are some adverse effects of SNRIs?
Nausea, sweating, dizziness, anxiety, sexual dysfunction, hypertension
May be more dangerous than SSRIs in overdose
What are the drug interactions with SNRIs?
No pharmacodynamic
Variable protein binding, CYP 2D6
What is mirtazapine? How does it work?
An atypical antidepressant
Blocks alpha 2 adrenergic receptors, thus increasing norepinephrine release
Potent histamine blocker
Low affinity for muscarinic, alpha 1 adrenergic receptors
What are the adverse effects of mirtazapine?
Sedation (may be helpful in sleep disturbances), weight gain
Less chance of sexual side effects
What is bupropion? How does it work?
An atypical antidepressant
Unknown mechanism (doesn’t inhibit NE or serotonin uptake)
Weakly blocks dopamine reuptake, mild stimulant
Low affinity for muscarinic, alpha 1 or histaminergic receptors
What can bupropion be used to comorbidly treat with depression?
Fatigue, poor concentration, ADHD
What are the adverse effects of bupropion?
Nausea, headache, dizziness, insomnia, seizures*
Much lower incidence than with TCAs
No sexual dysfunction, weight gain, sedation
What are the drug interactions with bupropion?
Meds that lower the seizure threshold, L-Dopa
CYP 2D6 inhibitor
What are the 1st line treatment options for major depression?
SSNRI, SNRI
If it fully remits, maintain for 4-6 months
What should be used as 2nd line treatment options?
No response: Switch to different SSRI, SNRI, bupropion, mirtazapine
Partial response: switch or augment atypical antipsychotics, bupropion
