Antidepressant and Stabilizers Flashcards
Depression
An effective disorder characterized by loss of interest and pleasure in daily activities
Symptoms of Depression
Diminished interest in activities Decreased concentration, indecisiveness Loss of energy, fatigue Guilt, Excessive guilt, feelings of worthlessness Loss or gain of appetite Sleep insomnia or hypersomnia Psychomotor Suicide
Tricyclic Antidepressants
Effectively relieve depression with anxiolytic and analgesic action
Pharmacologic Properties
- Block presynaptic NE reuptake transporter
- Block presynaptic 5-HT reuptake transporter
- Block reuptake histamine transporter
Block postsynaptic ACh receptor
Have virtually no effect of DA rtransporter
Not selective
Ex. Imipramine(Tofranil), Clomipramine (Anafranil)
Effects of Blocking Transporters
ACh blockade leads to dry mouth, confusion, blurry vision, and mental confusion
Histamine blockage leads to drowsiness and sedation
Can induce cardiac depression and increased electrical irritability, can be fatal during/after OD
Pharmacokinetics TCA
Well absorbed upon oral absorption Relatively long half lives Metabolized in the liver Converted into intermediates that were then detoxified Readily crosses the placenta
Clinical Limitation TCA
Slow onset of action, 2-4 weeks for antidepressant effect to appear
Wide variety of effects on CNS( adverse effects)- can impair attention, memory motor speed and dexterity
Cardiotoxic and potentially fatal in overdoses
Notriptyline
Superior pharmacologic properties compared to all other TCA as psychotropic
Potent as an NRI and has good TI
Safe to combine with MAOI or SSRI
Advantage when treating refractory patients who may require antidepressant drugs
Second Generation Trazedone
Not a potent blocker of NE or 5-HT, its active metabolite blocks a class of 5-HT receptors
Second Generation Bupropion
Selectively inhibits DA reuptake, used for ADHD
Side effects include nausea, anxiety, restlessness, tremors, insomnia
Clomipramine
Sturcutrally a TCA but exerts inhibitory effects on 5-HT reuptake
Desmethyclomipramine
Active metabolite, Mixed 5-HT and NE reuptake inhibitor, used to treat OCD, depresion, panic disorder, phobia disorder
Venlafaxine
Mxed 5-HT and NE reuptake inhibitor, but also inhibits reuptake of DA and improves psychomotor and cognitive function
SSRI
Fluoxetine (Prozac) first released in 1987
Increases the amount of serotonin available to stimulate post synaptic receptors
Can treat depression ADHD, obesity, alcohol abuse, childhood anxiety
Long term- facillitate increased survival and grown of neurons via action on the cAMP response element binding protein and brain derived neurotrophic factor (BDNF)
Reduce glucocorticoids- stress hormone
BDNF lower in depressed patients
Repair neurons, increase neurogenesis, primarily in hippocampal and frontal regions- accounts for the delay in therapeutic response to antidepressant therapy
Nefazodone (Serazone)
Unique antidepressant, resembles TCA as an inhibitor of 5HT and NE reuptake, no therapeutic superiority over TCA and SSRI
Mirtazapine (Remeron)
Increases noradrenergic and serotonergic neurotransmission by blocking alpha autoreceptors and heteroreceptors, a potent antagonist, rapidly absorbed orally
Monoamine Oxidase Inhibitor
1 out of 2 enzymes that break down 5HT and NE
MAO-A inhibition causes antidepressant activity
MAO-B inhibition- causes side effects
Allows more neurotransmitter in synapse
Potential for serious side effects and potentially fatal interactions with other drugs and food
Behavioral Therapies
non-pharmacological treatment useful in treating some depression
Number of well controlled studies is limited, so not clear how effective they are long term
More useful when combining pharmacologic therapies
Exersize may also be helfpful
Medications often needed early in the treatment plan, manage overt symptoms
- As symptoms become less intense, more receptive to behavioral therapy
- Medications eventually reduced, behavioral therapies increased
Long term maintenance with low dose is necessary for some
Electroconvulsive Therapy
Used for treatment resistant depression
ECT safest quickest most effective treatment for moderate to severe depression
Patient given a muscle relaxer and put under brief anesthesia
Electrical current passed through temples causing a brief seizure
ECT Use
begins with several times a week
Shift to weekly, then monthly
Will often also need to take an antidepressant
Given unilaterally on left side, protects memory and cognitive function on right
Electric pulse is briefer and causes fewer side effects
ECT Side effects
Confusion Disorientation Memory loss - Mostly gone after treatment ECT does not cause brain damage, nor permanent dysfunction. Actually increases cerebral functioning of patients with severe dysfunction
Repetitive Transcranial Magnetic Stimulation
- Rapidly changing electromagnetic induction used to generate weak electrical currents that are targeted to specific regions of the brain
Causes both depolarization and hyperpolarization of neurons within current fields
Modest effect on depression- not as effective as ECT, but side effect profile better
Mania
Distinct period of abnormal and persisten elevated expansive or irritable mood
Must last at least 1 week
BPD Diagnosis
Distractibility Indiscretion( Excessive involvement n pleasurable activities with the likelihood of painful consequences) Grandiosity (Inflated self esteem) Flght of ideas or racing though Talkativeness/Pressured speech Sleep Deficit
Hypomania
Same symptoms as bipolar disorder but shorter length of symptoms
Less severe impairment
Types of BPD
BPD1- Clear episodes of depression and mania
BPD2- less intense and unrecognized manic states
Cyclothymia- Chromic moods of hypomania and depression, often evolves into a more serious type
Bipolar Disorder Not Otherwise Specified- Largest group of individuals
Neurochem of BPD
BPD is progressive neurochemical disorder
Regional difference in neuronal density in hippocampus
Adrenergic-Cholinergic balance for hypothesis for mania
Can have abmormalities in orbitofrontal cortex and amygdala
Time Course of BPD
Initial cycle typically MDD
Recovery- Relapse
Rapid Cycling
Rapid- 4 episodes a year
Ultrarapid 5-364
Ultraradian > 365 episodes a year
Bipolar vs ADHD
Bipolar: More talkative than usual, pressure to keep talking, Distractibility, Increase in goal directed activity, or psychomotor agitation
ADHD: Talks excessively, Often easily distracted by extraneous stimuli, always “on the go” as if driven by a motor
COMORBID
BPD Treatment
Patient can either present with depression or mania
Misdiagnosed as unipolar depression or mania
Choice of treatment can depend on presentation and severity of disorder
Mood stabilizer likely to be more helpful over the long term
Mood Stabilizer vs Anti Depressant
Antidepressant can precipitate an episode of mania in BPD and presents with depression first
Mood stabilizers reduce cycling between the extreme states
Prevent future relapses into mania, mixed, or depressive symptoms
Lithium
Historically first effective treatment for bipolar
Introduced as sedative hypnotic
Significant side effects and blood levels should be monitored
Found in natural spring waters
Drugs with better side effect profiles are being found
Lack of medication adherence
Countries with higher levels of lithium in waters have lower levels of depression and suicide
Lithium Mechanism of Action
Alters cation transport across cell membrane in nerve cells and muscle cells
Influences reuptake of 5-HT and NE
Second messenger systems involving phosphaditylinositol cycle are inhibited
Post synaptic D2 receptor supersensitivity is inhibited
Inhibition of AKT/GSK3 beta signaling
Lithium and Grey Matter
Increases gray matter in BPD- areas that regulate attention, motivation, and emotion
Lithium Cautions
Take exactly as directed- DONT CHANGE DOSAGE
Don’t crush or chew tablets
Maintain hydration
Avoid changes in sodium content- can affect lithium toxicity
Limit caffeine intake- diuresis can increase lithium toxicity
narrow therapeutic range
Carbamazepine (Tegretol)
Effective as lithium, but not as protective
Some patients benefit from taking a combination of the two
Valproic Acid
Augments postynaptic action of GABA at its receptors
May enhance gene expression in critical brain circuit regions
Most effective in acute mania, mixed states, schizoaffective disorders and rapid cycling
Gabapentin
Anticonvulsant
Relieves symptoms of bipolar disorder, anxiety, certain types of neuropathic pain and substance abuse
Similar to valproic acid, except better analgesic
GABA analogue and increases intracellular brain GABA levels
Excellent PK profile
Tolerated, even at high doses
Adjunct medicine in patients who are resistant to more effective mood stabiizer, like lithium, valproate or lamotrigine
Pregabalin (Lyrica)
Derivative of Gabapentin
Approved for treating neuropathies and adjunct to treating partial seizures
Not approved to treat BPD
Lamotrigine
Not effective in acute manic episodes
Often in individuals who are unresponsive to other medications
Effective in maintenance and preventing relapse of depressive symptoms
Lamotrigine mechanism of action
Inhibits release of excitatory neurotransmitter, glutamate, in cortex and hippocampus
Accounts for antiepileptic, antimania and analgesic effects
Neuronal excitability is reduced in specific brain regions
May also be effective in brain injury patients because of glutamate inhibition
Lamotrigine Side Effects
Rash in 1 out of 500
Stevens-Johnson Syndrome- Epidermal necrolysis- can be fatal
Antipsychotic
Effective at treating mania, but little effect on depressive symptoms
Atypicals more useful in managing both
Olanzapine, risperidone and quetiapine have all had positive clinical trials
BPD and Drug Abuse
55% BPD patients also comorbid with drug abuse
