Bipolar Disorder and Schizophrenia Lecture Flashcards
Bipolar Disorder
Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks; Like depression, bipolar disorder is a mood disorder; The moods range from periods of extremely “up,” elated, and energized behavior (known as manic episodes) to very sad, “down,” or hopeless periods (known as depressive episodes); Prevalence: 1-1.5% of the population
Bipolar Disorder: Sign and Symptoms
Periods of unusually intense emotion, changes in sleep patterns and activity levels, and unusual behaviors. These distinct periods are called “mood episodes.” Mood episodes are drastically different from the moods and behaviors that are typical for the person. Extreme changes in energy, activity, and sleep go along with mood episodes.
Psychosis: Sometimes, a person with severe episodes of mania or depression also has psychotic symptoms.
a mental state, the person affected has lost contact with reality hallucination: false sensory perceptions
delusion: false beliefs held with absolute certainty
disruption in thought process
Schizophrenia is a primary psychotic condition
As a result, people with bipolar disorder who also have psychotic symptoms are sometimes misdiagnosed with schizophrenia.
Bipolar disorder : Treatment
- 1st line some atypical antipsychotic drugs: olanzapine,
rispridone, quetiapine, aripiprezole - 2nd line Li+ ion: therapeutic effects begin in ~ 5 d, require several wk.
- others antiepileptic drugs: e.g. valproic acid, carbamazepine, These also require several wk for full effects
• Social
– Support Groups
» DRADA (Depression and Related Affective Disorder Association)
» NDMDA (Depression and Bipolar Support Alliance)
– Rehabilitation and “habilitation”
How does Li+ act?
diagram
Lithium PK
– Lithium is given by mouth as the carbonate salt
– Li+ enters cells freely through several channels and
ion-coupled transporters that normally serve for Na+
– excretion by glomerular filtration but Li+ is nephrotoxic
self perpetuating toxicity!
Lithium - drug interactions
– diuretics reduce renal lithium secretion (enhanced re-absorption of Na+ and Li+ in proximal tubule)
– drugs reduce renal clearance (e.g.Ang II rec antagonists, NSAIDS)
– serotonin syndrome with SSRI or MAOIs
– ACE inhibitors increase serum lithium concentrations, although the precise mechanism is not understood
Lithium - ADR
Common!
– low dose: dry mouth, increased thirst and urination,
– Li+ is quite poisonous at higher doses
– overdose: coma convulsions, loss of consciousness,
death
– long-term:
» hypothyrodism,
» diabetes insipidus
– narrow therapeutic index (approximately 0.5-1.5 mmol/l)
above 1.5 mM it produces a variety of toxic effects.
– regular monitoring of [Li+]plasma
– modified release formulations to avoid high Cmax
Lithium - cautions
– pregnancy – probable teratogenesis
– renal and thyroid function tested before starting therapy
Schizophrenia
a severe psychotic disorder affecting thinking, feeling,
– deficits in cognitive function (e.g. attention, memory)
– together with anxiety, guilt, depression and self punishment
– leading to suicide attempts in up to 50% of cases, about 10% of which are successful
– usually starts between the ages of 15 to 35;
– affects about 1% people during their lifetime;
Schizophrenia causes
Genetic links - one in ten people with schizophrenia
has a parent with the condition
Damage - to the brain during pregnancy or birth
viral damage to fetal brain
Stress - Highest rates among urban poor
Recreational drugs -ecstasy, LSD, amphetamines (speed), cannabis and crack
Symptoms of Schizophrenia
Positive symptoms:
- Delusion
- Hallucinations
- Thought disorder
- Abnormal, disorganised behaviour
Negative symptoms:
- Withdrawal from social contacts
- Flattening of emotional responses
- Emotional responses out of context
- Reluctance to perform everyday tasks
Brain abnormalities - schiz
• Enlarged Ventricles
– Implies loss of brain cells
– Correlate with
» Poor performance on cognitive tests
» Poor premorbid adjustment
» Poor response to treatment
• Reduced activity in prefrontal cortex
– Many behaviors disrupted by schizophrenia (e.g., speech,
decision making) are governed by prefrontal cortex
– Individuals with schizophrenia show impairments on
neuropsychological tests of prefrontal cortex (e.g., memory)
– Individuals with schizophrenia show low metabolic rates in prefrontal cortex
Dopamine hypothesis
• Over-activity of dopamine
– Six times as many D4 dopamine receptors as normal brains
• May intensify brain signals and lead to positive symptoms
• Amphetamine (very high doses) paranoia, delusions, auditory hallucination
• Also exacerbates symptoms of schizophrenia.
• Phenothiazines (incl. chlorprom.) & all other typical neuroleptics block D2 receptors and alleviate (+) symptoms.
Principle dopaminergic tracts
- Nigrostriatal tract- (extrapyramidal pathway) begins in the substantia nigra and ends in the caudate nucleus and putamen of the basal ganglia
- Mesolimbic tract - originates in the midbrain tegmentum and innervates the nucleus accumbens and adjacent limbic structures
- Mesocortical tract - originates in the midbrain tegmentum and innervates anterior cortical areas
- Tuberoinfundibular tract - projects from the arcuate and periventricular nuclei of the hypothalamus to the pituitary
Conventional anti-psychotic drugs - mechanism
Blockade of CNS dopamine receptors in mesolimbic pathways
–High affinity for the family of D2 receptor
BUT – response takes weeks to develop –adaptive response?
also D1, 5-HT2, a-adrenergic, histamine antagonists
Conventional anti-psychotic drugs - PK
Rapidly absorbed from the gut but undergo extensive first-pass metabolism
Elimination is by metabolism in the liver
Depot formulations have been developed
as adherence to treatment is often poor
e.g. – flupentixol decanoate
– zuclopenthixol decanoate
Conventional antipsychotic drugs examples
- 1953 chlorpromazine (Thorazine)
- 1958 trifluoperazine (Stelazine)
- 1958 perphenazine (Trilafon)
- 1959 fluphenazine (Prolixin)
- 1959 thioridazine (Mellaril)
- 1967 haloperidol (Haldol)
- 1967 thiothixene (Navane)
- 1970 mesoridazine (Serentil)
- 1975 loxapine (Loxitane)
- 1977 molidone (Moban)
- 1984 pimozide (Orap)
Conventional anti-psychotic drugs
• ADR
– Extrapyramidal effects (extrapyramidal motor disturbance)
arise from D2 receptor blockade in the nigrostriatal pathways;
occur in >50% patients, but reversible;
– Drowsiness and cognitive impairment;
– Antimuscarinic effects: dry month, constipation, confusion, etc;
– alpha1-adrenoceptor antagonism: postural hypotension, etc;
– Hypothermia
– Reduced seizure threshold
– Hypersensitivity
– Weight gain
– GI disturbance
– Prolonged Q-T interval, leading to ventricular arrhythmias
– Neuroleptic malignant syndrome
– Withdrawal symptoms
Extrapyramidal effects
Antipsychotic drugs block DAergic neurons in mesolimbic pathway
BUT DAergic neurons also in nigrostriatal pathway. This
pathway regulates the “extrapyramidal system” which contributes to the control of movement. Acute dystonia tongue protrusion torticollis oculogyric crisis
Akathisia –restlessness
Pseudoparkinson
Tardive dyskinesia (with prolonged use and esp. in the elderly)
Evaluation of Dopamine Theory
• Dopamine theory doesn’t completely explain
disorder
– Antipsychotics block dopamine rapidly but symptom
relief takes several weeks
– To be effective, antipsychotics must reduce dopamine
activity to below normal levels
• Other neurotransmitters involved:
– Serotonin
– GABA
– Glutamate
» Medication that targets glutamate shows promise
Glutamate hypothesis
• NMDA receptor antagonists such as Phencyclidine (PCP), Ketamine, can
produce both positive and negative psychotic symptoms – in contrast to
amphetamine which produced only positive symptoms
• PCP, a dissociative anesthetic, NMDA antagonist (blocks Ca2+ channel)
– Auditory hallucinations
– Depersonalization
– Delusions
“atypical” antipsychotic • Mechanism
– Blocks serotonin, to a lesser degree, dopamine receptors
– Also blocks receptors for Na, histamine, acetylcholine
“atypical” antipsychotic - examples
- 1990 clozapine Clozaril
- 1994 risperidone Risperdal
- 1996 olanzapine Zyprexa
- 1997 quetiapine Seroquel
- 2001 ziprasidone Geodon
- 2002 aripiprazole Abilify
- 2003 risperidone MS Consta
“atypical” antipsychotic - efficacy
- Effective for positive symptoms: =/> typical antipsychotics
- Effective for negative symptoms: > typical antipsychotics
- Clozapine is more effective than conventional antipsychotics in treatment resistant patients
