Week 3 (Vision and Psychosis) Flashcards
Exposure and symptoms of PTSD
Exposure: traumatic event (experienced, witnessed); response (intense fear, helplessness, horror)
Symptoms: re-experiencing (nightmares, flashbacks); avoidance (avoid reminders, emotional numbing); autonomic arousal (exaggerated startle, hypervigilance)
Brain regions involved in PTSD
Amygdala has increased activation (does fear recognition, fear memory, HPA regulation)
Hippocampus has decreased activation during memory tasks and decreased size (does declarative/episodic memory and HPA regulation)
Medial prefrontal cortex has decreased activation and decreased size (normally does inhibitory control of amygdala, etc)
Hypothalamic-pituitary-adrenal (HPA) axis has increased activation (does stress, etc)
Also nucleus accumbens does MPFC and amygdala circuits
Amygdala functions
Aggression
Fear (expressing fear and identifying fear in others)
Anger
Face recognition
Social hierarchy
Also influences autonomic and endocrine functions and contributes to stress and disease: increases BP, HR, cortisol
Hippocampus and medial temporal lobe functions
Formation of new memories
Spatial navigation
Stress response and feedback regulation of glucocorticoid secretion
What does PTSD ultimately lead to?
Autonomic dysregulation
Altered stress response and dysregulated cortisol levels
Increased activation of amygdala, decreased inhibition by hippocampus, decreased inhibition by mPFC all cause increased cortisol in PTSD
Activity of medial prefrontal cortex (mPFC) in PTSD
Medial prefrontal cortex usually inhibits the amygdala
In PTSD, mPFC does not inhibit amygdala, so the amygdala is over-active
Interoceptive vs. exteroceptive stimuli
Interoceptive stimuli: derive from inside the body (gut, heart, etc); cause amygdala-dependent associative learning
Exteroceptive stimuli: derive from outside body (sounds, sights, etc); cause hippocampal-dependent explicit memory
Note: these two interact to provide immediate conscious experience of emotional feelings (working memory in prefrontal cortex)
Neurochemical changes in PTSD
NE increased –> increased BP, HR, etc
5HT dysregulated
Modification of memories
Memories require reconsolidation every time they are recalled and this reconsolidation requires protein synthesis
Recalled memories can be modified during reconsolidation
Treatment for PTSD is using this (behavioral therapy, pharmacological manipulation or both)
What determines whether someone develops PTSD
Genes and environment, of course
Person’s physical and emotional reaction to the traumatic event, NOT the absolute magnitude of the event
Extreme fear, horror or helplessness, and preexisting anxiety predicted PTSD
Complex PTSD
Different symptoms if traumatic event was single event (assault) compared to ongoing trauma (child abuse)
Early traumatic events increased vulnerability to genetic risk for substance abuse, depression
Prolonged traumatic events in childhood interfere with development of emotional regulation and symptoms may look like personality disorders
Acute stress disorder
Seen in first 30 days after acute stressor
Dissociation is key component
Thought to predict PTSD
Note: cannot be called PTSD until a month after the event
Observations about the development of PTSD after traumatic event
HR immediately after MVA is independent predictor of PTSD
Amount of morphine given to burn patients is inversely correlated with risk for PTSD afterward (give more morphine!)
Suggested that early interventions to reduce arousal might reduce intensity of memory consodlidation about traumatic event
Pharmacological treatment for PTSD
Mostly symptomatic
Beta blockers
SRIs for anxiety, phobias, PTSD
Benzos acutely (not long-term!)
Psychotherapy for PTSD
Trauma focused CBT is the most tested
Components of treatment:
Reduce autonomic arousal with relaxation or meditation training (decrease helplessness)
Confront reminders and learn they are tolerable (desensitization so as to improve function)
Rework the trauma narrative (making it more about words and less about emotions)
Redefine what is safe
Continuum of CNS stimulant action
Increased alertness
Nervousness and anxiety
Stimulation of respiration and cardiovascular function
Convulsions and death
Glycine
Major inhibitory NT in the brainstem and spinal cord
Has motor and sensory functions
Binds inhibitory glycine receptors (ligand-gated Cl channels) to activate Cl- ion conductance and cause hyperpolarization of the neuronal membrane
Required co-agonist along with glutamate for NMDA receptor
Subserves both inhibitory and excitatory functions in CNS
Strychnine
Glycine antagonist
Primarily affects motor nerves in spinal cord which control muscle contraction
Convulsant properties: causes tonic hyperextension of the body and limbs, with back arched (opisthotonos)
All voluntary muscles in full contraction with strychnine poisoning; exaggerated reactions to all sensory stimuli
Plant alkaloid historically used as pesticide (rat poison)
General effects of psychomotor stimulants
Increase in behavioral and motor activity
Increase in alertness and disruption of sleep
Pupil dilation, shift in blood flow from skin and organs to muscle, increased body temperature
Increase in blood pressure and heart rate
Increased O2 and glucose levels in the blood
Side effects of anxiety, insomnia and irritability
Actions at DA, 5HT and NE synapses
Methylxanthines
Psychomotor stimulant
Xanthine is a purine base found in most human body tissues and fluids; a product on pathway of purine degradation that is then turned to uric acid by xanthine oxidase enzyme
Ex: caffeine, theophylline, theobromine
Caffeine
Adenosine antagonist (remember A1 adenosine receptors normally inhibit adenyl cyclase, decrease intracellular cAMP)
At high concentrations is a phosphodiesterase inhibitor
Orally absorbed and maximal plasma levels attained at ~30 min
Distributed throughout all body compartments, can reach placenta and pass into breast milk
Hepatic metabolism
Plasma half life is 3-6h
Pharmacologic effects of caffeine
CNS stimulation: increases alertness and defers drowsiness and fatigue
CV: increases HR and coronary blood flow
Respiratory: relaxes smooth muscle of bronchioles at high dosages
Gastric mucosa: stimulates secretion of HCl from gasatric mucosa
Diuretic
Adverse effects of caffeine
Anxiety, insomnia, precipitation of panic attacks, tachycardia, tremors, increase in urination frequency
Varying degrees of tolerance
Psychological and physical dependence
Withdrawal: headache (not relieved by aspirin), fatigue, impaired psychomotor performance and depression; appears 12-24h after last dose and peaks at 20-48h and lasts 1 week
Clinical uses of caffeine
Headache, migraine (vasoconstrictive actions)
Formerly treatment for asthma (theophylline) but not anymore because inhaled corticosteroids more effective
Relative potencies: theophylline > caffeine > theobromine
Controlled substances
Schedule I controlled substances: no accepted medical use in US, high potential for abuse (heroine, LSD, MJ, peyote, methaqualone, MDMA/ecstasy)
Schedule II controlled substances: high potential for abuse which may lead to severe dependence (hydromorphone, methadone, meperidine, oxycodone, fentanyl, morphine, opium, codeine, amphetamine, methamphetamine, methylphenidate, amobarbital, glutethimide, pentobarbital)
Schedule III controlled substances: less potential for abuse, moderate or low physical dependence, high psychological dependence (<15mg hydrocodone like Vicodin, <90mg codeine like Tylenol+Codeine, buprenorphine, benzphetamine, ketamine, depo-testosterone)
Schedule IV controlled substances: low potential for abuse (alprazolam/Xanax, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, triazolam)
Schedule V controlled substances: low potential for abuse (limited quantities of certain narcotics)
Amphetamines
Indirectly acting sympathomimetics: release and block reuptake of NE, DA and 5HT so increase NT levels
At high doses, MAO activity inhibited (to also increase NT levels)
Clinical uses: narcolepsy, ADD, not for weight loss
Metabolized by CYP450-mediated oxidation to phenylacetone then to benzoic acid
D-methamphetamine and D-amphetamine (D-isomer more potent than L-isomer)
Adderall (amphetamine) of Ritalin (methylphenidate) for ADHD
Ephedrine, pseudoephedrine (mixed)
Indirectly acting sympathomimetics
Alpha and beta adrenergic agonists AND block reuptake of NE, DA
Ephedrine more potent than pseudoephedrine
Methamphetamine
Indirectly acting sympathomimetics: release and block reuptake of NE, DA and 5HT so increase NT levels
Methamphetamine metabolized to amphetamine (major) and 4-hydroxymethamphetamine (minor)
Prolonged action due to long half life (10-12h)
25% of METH and AMPH eliminated by renal ion trapping
CNS stimulant: wakefulness, mood elevation, improves performance on dull repetitive tasks (does NOT facilitate learning), appetite suppression
CV stimulation
Tolerance occurs rapidly (tachyphylaxis)
Dependence: withdrawal includes prolonged sleep, lassitude, fatigue, depression, intense hunger (hyperphagia)
Adverse reactions of amphetamines
Psychiatric: dizziness, tremor, hyperirritability, insomnia, hyperthermia, chronic use can produce paranoid psychosis, addiction
Neurological: cerebral edema, hemorrhage; chronic use associated with neurotoxicity (long-term DA deficits)
CV: tachycardia, palpitations, arrhythmias, HTN, headache, stroke
GI: anorexia, nausea, vomiting
Drug interactions: hypertensive crisis with MAO inhibitors
Drugs to treat ADHD
ADHD characterized by short attention span, restlessness, impulsivity and hyperactivity
Amphetamine (Adderall): psychomotor stimulant that promotes release and/or blocks reuptake of DA and NE
Methylphenidate (Ritalin): psychomotor stimulant that promotes release and/or blocks reuptake of DA and NE
Atomoxetine: non-psychomotor stimulant; selective NE reuptake inhibitor (NRI); less abuse potential but black box warning for increased suicidal thoughts and behaviors
Methylphenidate
Ritalin or Concerta (long-acting)
Blocks reuptake of DA and NE
Absorption orally and max plasma level 1-3 hours after ingestion
Hepatic metabolism, half life of 2-7 hours
Similar pharm effects to amphetamine but less potent, fewer peripheral and cardiovascular effects
Adverse reactions: insomnia, restlessness, talkativeness, behavioral disturbances
Appetite suppressants
Phentermine: amphetamine analog but less potent
Topiramate + phentermine combination (Qsymia)
Modafinil (Provigil)
Mechanism unclear: increases release of DA, may involve hypocretin, histamine, GABA and glutamate to increase activation of NE neurons in locus ceruleus, leading to more “wakeful state”
Wakefulness promoting agent (not a classic amphetamine-like stimulant)
Used for narcolepsy and other sleep disorders; also for ADHD and Alzheimer’s
Cocaine
Indirectly acting sympathomimetic
Blocks reuptake of DA (centrally), NE (peripherally) to overall increase NT concentrations
Absorption: smoking gives faster entry to brain and higher drug levels than IV administration
Distribution: initially distributed to highly perfused tissues (brain) then redistributes throughout body
Metabolism: short half life 45 min because metabolized by esterases; smoking only give 5-10 min high; major metabolites in urine (85-90% of dose) are benzoyl ecgonine and ecgonine methyl ester
Pharmacologic effects of cocaine
CNS: similar to methamphetamine; dependence
Peripheral effects: local anesthetic, vasoconstriction
Tolerance develops rapidly to CNS effects and other effects too at different rates/degrees
Only clinical use is local anesthetic
Adverse effects of cocaine
No correlation between euphoria and adverse effects
Can occur at any time and after any route of administration
OD is fatal
Seizures, hyperthermia, respiratory arrest, cardiac (increased HR and BP, angina, MI, arrhythmias), cerebral hemorrhage and stroke, ischemic bowel
Cocaine abuse
Binge user, not daily
Less euphoria during late stages of binge: irritability, dysphoria, anxiety, paranoia, depression
User may take cocaine until they run out
Eventually become physically exhausted but have insomnia and take CNS depressants to fall asleep then sleep for 8-40 hours (“crash”) and wake up extremely hungry
Craving for cocaine returns, individual becomes bored/anhedonic, and when try to give up cocaine have cravings triggered by environmental cues
MDMA (ecstasy)
Releaser and/or reuptake inhibitor of presynaptic 5HT, DA, NE
5HT probably causes pro-social, emotional effects and also triggers release of oxytocin and vasopressin (love, trust, sexual arousal, etc)
Synthetic, psychoactive drug similar to stimulant amphetamine and hallucinogen mescaline
Produces feelings of increased energy, euphoria, emotional warmth and empathy toward other and distortions in sensory and time perception
Metabolism: half life 8-9h; 2 metabolic pathways (to MDA or to benzoic acid derivatives)
Adverse effects of MDMA
Many of same physical effects as cocaine and amphetamines (increase HR and BP)
At high doses can cause hyperthermia
MDMA intoxication (similar to serotonin syndrome): neuromuscular effects (hyperreflexia, clonus, tremor), autonomic effects (hyperthermia, tachycardia) and mental effects (agitation, confusion, anxiety)
Surge of serotonin caused by MDMA reduces its brain levels causing negative after-effects: confusion, depression, sleep problems, drug craving, anxiety (may occur soon after taking the drug or during the days or weeks after)
“Bath salts”
Contain one or more synthetic chemicals related to cathinone (amphetamine-like stimulant found in Khat plant)
Mephedrone, MDPV, methylone are three main components of bath salts (structures similar to MDMA and amphetamine)
Act on NE, DA and 5HT presynatptic terminals as indirectly acting agents to increase NT concentrations in the synapses
Increased energy, empathy, openness, increased libido
Adverse effects: cardiac, psychiatric and neurological
Hallucinogens
LSD
Psilocybin
Mescaline
LSD (lysergic acid diethylamide)
Semisynthetic psychedelic drug of ergot family
Probably mixed 5HT2/5HT1 partial agonist
Hallucinations due to high affinity for 5HT2 receptors (similar to mescaline and psilocybin)
Lasts 6-12 hours; plasma half life 5h with peak plasma concentration 3 hours after
Causes sensory alterations, pseudo-hallucination, alterations of affectivity (euphoria, dysphoria, anxiety, mood swing)
Psychological effects: altered cognitive and emotional processes, dilated pupils, closed/open eye visual experiences, hallucinations, synesthesia, altered sense of time, spiritual experiences, loss of filtering, bad trip, flashbacks
Stimulant-psychosis
Can result from use of stimulant drugs in abusers or in patients taking therapeutic doses under medical supervision
Most common stimulants involved are amphetamines and cocaine, but bath salts produce severe psychotic episodes faster, more intense and longer lasting
Symptoms are similar to organic psychosis/schizophrenia: hallucinations, delusions, thought disorders and in extreme cases catatonia
Psychosis
Generic term that describes some impairment in “reality testing” resulting in the inability to distinguish reality from fantasy
Hallucination vs. illusion
Hallucination: sensory perception that has compelling sense of reality of a true perception but that occurs without external stimulation of relevant sensory organ
Illusion: misperception or misinterpretation of real external sensory stimulus and often occurs in relation to substance intoxication
Auditory verbal hallucinations
Most common hallucination in psychotic disorders is auditory verbal hallucination (hearing a voice)
Voice-hearing probably heterogeneous phenomenon with multiple mechanistic pathways
Neuroimaging studies implicate L temporal lobe and auditory cortex and R hemisphere homologue of Broca’s area in etiology of auditory verbal hallucinations
Suggest abnormal generation of internal verbal experiences coupled with delateralized processing errors that result in perceptions of non-volitional, external and auditory speech
How auditory verbal hallucinations may be formed?
Inner speech, memories, thoughts may be excessive, negative or otherwise abnormal –> errors in processing –> non-volitional, non-self, auditory, external
What must hallucinations be differentiated from?
Normal thoughts, inneer speech = verbal thinking
Ruminations, obsessions = self, but ego-dystonic
Thought insertion, illusions = non-self
Delusions
A fixed, false belief
False belief based on incorrect inference about external reality that is firmly sustained despite what almost everyone else believes and despite what constitutes incontrovertible and obvious proof or evidence to the contrary. The belief is not one ordinarily accepted by other members of the person’s culture or subculture (ie not an article of religious faith)
Themes of delusions
Persecution/paranoia (ideas of reference)
Grandiosity (special powers, spiritual, erotomania)
Somatic (control, hypochondriacal, infection, infestation)
Misidentification: capgras (others have been replaced by imposters), fregoli (persecutor with many faces), cotard (nihilistic/negation)
Cognitive features of delusions
Preoccupation
Affective valence (distress, worry, fear, etc)
Unwarranted and excessive conviction: creative explanations for anomalous experiences, evaluations based on not enough evidence (increased impulsivity), evaluations based on poorly selected evidence (decreased filtering), difficulties distinguishing coincidence vs. causality, few opportunities for “social” reality testing
Psychosis and dopamine
Psychosis as a state of aberrant “salience” mediated by dopamine
Excess mesolimbic DA results in heightened “saliance” (neutral/cold stimula –> relevant/hot stimuli)
Abnormal salience of external stimuli –> delusional thinking
Abnormal salience of internal stimuli –> hallucination
DA agonists and stimulants result in psychosis
Antipsychotic medications work by blocking DA transmission
Salience decreased with antipsychotic therapy
DDx of hallucinations and/or delusions (aka psychosis)
No mental illness
Malingering
Mania
Major depressive episode
Dementia
Delirium
Non-psychiatric brain disorder (seizure, tumor, infection, endocrine, etc)
Drug-induced psychosis
Substance intoxication:
Hallucinogens (visual distortions and hallucinations)
Psychostimulants (paranoia, illusions, hallucinations)
Alcohol withdrawal (VH)
Glutamatergic drugs (AVH, delusions)
Solvents (VH)
Cannabis (mild paranoia)
Medications (DA agonists, steroids)
Symptomatic domains in schizophrenia
Positive
Negative: affective flattening, alogia, avolition-apathy, anhedonia-asociality
Disorganized: tangential, circumstantial, loosening of associations
Disorganization
Disorganization as part of “thought disorder” that may reflect diminished hemispheric lateralization of language and disruption of semantic networks
Stilted, overly formal speech (“problems with anthropological friction and synchronization of the societal freeway…”)
Loosening of associations, illogicality, incoherence
Neologisms (“dramastic,” “schizophrenzyism”)
Concreteness/lack of abstractions (“the glass will break”)
Negative symptoms
Affective flattening: poor eye contact, decreased spontaneity, emotional withdrawal
Alogia: impoverished thinking, speech latency, thought blocking, decreased abstract thought
Avolition-apathy: decreased motivation, anergia, passivity
Anhedonia-asociality: decreased pleasure (anticipatory > consummatory), decreased social drive
Note: negative symptoms found in other conditions such as depression but patients with schizophrenia who have negative symptoms are not depressed
Primary vs. secondary negative symptoms
Primary negative symptoms: core features of schizophrenia and may be mediated by aberrant DA and glutamatergic neurotransmission; do not respond well to antipsychotic therapy and “deficit syndrome” associated with poorer social/occupational function, quality of life and overall outcome
Secondary negative symptoms: can be caused by positive symptom exacerbation, depression, medical illness, medication side effects, psychosocial/environmental factors
DSM-IV Criterion A
Two of more of the following 5 symptoms:
1) Delusions (positive symptoms)
2) Hallucinations (positive symptoms)
3) Disorganized speech (disorganized thinking)
4) Grossly disorganized or catatonic behavior (disorganized thinking)
5) Negative symptoms
Primary brain/CNS tumors
Meningioma (30%)
Glioblastoma (20%)
Pituitary adenoma (6-20%)
Intra-axial vs. extra-axial tumors
Intra-axial (brain parenchyma): glioblastoma
Extra-axial (not brain parenchyma): meningioma
Brain tumors in children
Pliocytic astrocytoma (cerebellum)
Medulloblastoma (cerebellum)
Craniopharyngiomas (suprasellar)
Germinoma (pineal gland/hypothalamus)
Pituitary adenomas
Other gliomas
Neurofibromatosis Type 2 (NF 2)
Mutation in Merlin/neurofibromin2/schwannomin which is membrane-cytoskeleton scaffolding protein that may be associated with contact-mediated growth inhibition and may be linker for outside cues to cytoskeleton
On chromosome 22
2 cerebellopontine angle vestibular schwannomas
Bilateral CN VIII schwannomas diagnostic of NF2
Can have meningioma (psammoma bodies), schwannoma (Verocay bodies), ependymoma (perivascular pseudorosettes)
All 3 tumors can be cured by resection
In contrast, NF 1 is associated with neurofibromas and pliocytic astrocytomas
Meningiomas
Mostly (80%) benign Grade I
Extra-axial (meningeal)
Association with NF2
Histology: whorls, nuclear pseudoinclusions, psammoma bodies
All grades can recur and Grade 3 can metastasize
Common secondary (metastatic) brain tumors
Lung, breast, renal, melanoma, GI (colon)
Carcinomas are epithelial and therefore express keratin in contrast to GBMs which are GFAP+
How are biomarkers used for brain tumors?
Biomarkers can potentially be tested to determine whether therapeutic agent will be effective
Some biomarkers are prognostic
MGMT (DNA repair enzyme) is an example of a biomarker, and if low MGMT in tumor, will be susceptible to Temodar
IDH mutation
Common to low grade astrocytomas, oligodendrogliomas and mixed gliomas, as well as secondary glioblastomas that devolve from low grade tumors
Rare in primary GBMs but common in secondary glioblastoma
Glioblastoma
Astrocytic tumor with necrosis, vascular proliferation, mitoses
High grade, aggressive infiltrative intra-axial tumor (survival only 14 months)
Primary GBM: patient presents as GBM Grade IV
Secondary GBM: evolves from low grade glioma (Grade II, III)
Butterfly glioma involves both hemispheres
Epidemiology of schizophrenia
<1% of population
Risk increases with urbanicity, migration, winter births, obstetric complications, 1st/2nd trimester maternal infection (influenza, rubella, T. gondii), advanced paternal age and cannabis use
Slightly more males are schizophrenic than females
Genetics of schizophrenia
Heritability: most cases are sporadic (1/3 with FHx), 80% variance due to genetics, 50% among monozygotic twins, 10-15% with dizygotic twin or 1st degree relative
Polygenetic disease with evidence for many different chromosomal abnormalities and candidate genes (DRD1, NRG1, G72, COMT, DISC1, DTNBP1, RGS4)
Epigenetics may play a role
Interaction of genes with environment (fetal hypoxia, infection, etc)
Brain abnormalities associated with schizophrenia
Enlarged ventricles, reduced whole brain/grey matter volume, reduced hemispheric asymmetry, cortical volume loss, white matter disconnectivity, excessive synaptic pruning, sensory gating (P300, PPI) abnormalities, increased presyn DA synthesis, increased striatal DA receptor density, decreased N-acetyl aspartate, decreased glutamate receptors
However, no single common genetic, structural, or neurochemical “lesion” has been found
Age of onset of schizophrenia
Males: 20-24
Females: 25-29
Course of schizophrenia
Premorbid risk: genetic, environmental, social, etc
Prodrome: nonspecific symptoms, functional decline
Diagnosis: positive symptoms, chronicity
By definition, symptoms must be present continuously for at least 6 months; thought spontaneous recovery can occur, in the vast majority of cases, schizophrenia does not completely resolve, even with treatment and there is no “cure” for schizophrenia
Mortality is increased with schizophrenia (increased suicide, accidents, and medical morbidity) with lifespan shortened by 10-15 years
Schizophreniform and brief psychotic disorder
NOT schizophrenia because not for 6 months
Schizophreniform < 6 months
Brief psychotic disorder < 1 month
Favorable predictors of overall course of schizophrenia
Acute onset
Later onset
Onset with precipitating event
Good premorbid functioning
Lack of negative and cognitive symptoms
Female
Mood symptoms
Psychosocial support
Specific cognitive symptoms of schizophrenia
Vigilance/sustained attention
Processing speed
Memory (immediate and “working” memory, secondary memory, verbal memory)
Verbal fluency (word generation)
Executive function (volition, planning, set-shifting)
Social cognition (emotional processing, theory of mind, etc)
Effect of cognitive impairment on schizophrenics
Cognitive impairment can be subtle, but deficits can be as large as 2 standard deviations from normal
Cognitive deficits most predictive of functional (vocational/interpersonal) impairment and quality of life
Cognitive symptoms of schizophrenia are present well before onset of the full-blown disorder
Mild cognitive symptoms associated with schizophrenia also found amont non-affected first degree relatives
Cognitive symptoms are therefore ideal candidates for “endophenotypes” of schizophrenia (subclinical, objectively quantifiable traits that are associated with the illness in the general population; heritable, co-segregating and increased prevalence within families)
Cognitive symptoms respond only modestly to antipsychotic treatment
Current drug development in schizophrenia focuses on putative “cognitive enhancers” as adjunctive interventions
Initial workup when schizophrenia is suspected
H&P
Basic labs (CBC, chemistries, RPR, TSH, U/A)
Urine drug/tox screen (cocaine, amphetamines, cannabinoids, opiates, benzodiazepines, hallucinogens, phencyclidine, ketamine, MDMA, alcohol)
Neuroimaging for first-episode psychosis, children and elderly
Antipsychotic medications for schizophrenia
Dopamine D2 antagonists
On treatment for entire life
1st and 2nd generation drugs differ in terms of side effects (more extrapyramidal side effects with 1st gen)
Side effects: subjective dysphoria, motoric toxicity (restlessness, parkinsonism, tardive dyskinesia), metabolic side effects; so much carefully monitor
1st gen: haloperidol, fluphenazine, thiothixene, perphenazine, trifluoperazine, loxapine, chlorpromazine, thioridazine
2nd gen: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, iloperidone, asenapine, lurasidone
Response to antipsychotic treatment in schizophrenics
“Antipsychotic response” defined as 20% reduction in symptoms
Approx 30% of patients with schizophrenia do not respond to antipsychotic treatment
Clozapine is most effective antipsychotic medication for non-responders, but also has most dangerous side effects (seizures, agranulocytosis, myocarditis, etc)
Effectiveness is routinely compromised by non-adherence (due to lack of insight, side effects, resistance) and substance abuse (50% lifetime prevalence)
Positive symptoms most responsive targets of antipsychotic therapy
Outcomes of pharmacological treatment for schizophrenia
Historically, good outcomes when patients living in supported housing and subsisting on disability income who is able to stay out of the hospital
“Recovery Model” now challenges these expectations and emphasizes reintegration into community with vocational and psychosocial rehabilitation
Psychotherapy for schizophrenia
For optimal outcome, must integrate psychotherapy with pharmacotherapy as well
Evidence-based interventions: social skill training, CBT, cognitive remediation, compliance therapy, acceptance and commitment therapy, assertive community treatment, family based services, supported employment, yoga
Delusional disorder
Delusions of at least 1 month’s duration
Apart from impact of delusion(s) or its ramifications, functioning is not markedly impaired and behavior is not obviously odd or bizarre
Lack of insight inherent to delusional thinking associated with non-treatment and poor overall prognosis
Schizoaffective disorder
Comorbidity of schizophrenia and mood disorder (major depression or bipolar I disorder)
Psychotic symptoms must be present for at least 2 weeks in the absence of prominent mood symptoms
Cluster A personality disorders
Remember, PDs not diagnosed if symptoms are better accounted for by an Axis I disorder (like schizophrenia)
Cluster A personality disorders lack full-blown psychotic symptoms, but share some thematic features with psychotic disorders and most are found at a greater rate among relatives of patients with schizophrenia (but schizoid PD patients do NOT have more relatives with schizophrenia)
Paranoid PD (suspicious, mistrustful, preoccupied, reads into things, bears grudges) –> Delusional Disorder
Schizotypal PD (ideas of reference, odd/magical beliefs, unusual perceptions, suspicious, inappropriate affect, social anxiety) –> Schizophrenia
Schizoid PD (solitary, detached, reclusive, anhedonic, indifferent to others, emotionally flat) –> negative symptoms
Chlorpromazine
First antipsychotic drug (made in 1950s)
Phenothiazines
Used as generic term for antipsychotics (aka antischizophrenics or neuroleptics) because many antipsychotic drugs have this chemical structure
Ex: chlorpromazine (Thorazine), thioridazine (Mellaril) and fluphenazine (Prolixin)
Positive and negative symptoms of psychotic disorders
Positive symptoms: exaggeration of normal function (abnormality, distortion, delusions, prominent hallucinations, impaired reasoning)
Negative symptoms: loss of function (catatonic behavior, flat or grossly inappropriate affect)
Dopamine hypothesis of schizophrenia
States that hyperactivity of central DA systems is responsible for the psychiatric state observed
Could be increased synthesis or release of DA, decreased degradation of DA cell levels, or supersensitive postsynaptic DA receptors
This hypothesis supported by findings that antipsychotic drugs block dopamine D2 receptors
Inconsistencies in this hypothesis: don’t start seeing antispychotic effects until 3-6 weeks after treatment (but D2 blockage occurs right after administering drug); clozapine (doesn’t have affinity for D2) still works well as antipsychotic
5 dopamine receptor subtypes
D1 and D5 receptors increase adenylyl cyclase activity
D2, 3, 4 receptors inhibit adenylyl cyclase activity
What determines the clinical potency of most antipsychotic drugs?
Ability to bind to D2 receptor (NOT ability to bind D1 receptor)
Serotonin hypothesis of schizophrenia
Based on interactions between hallucinogens (LSD) and 5HT in the brain at 5HT-2A receptors, particularly in locus ceruleus and cerebral cortex
Enhancement of glutamatergic transmission
Glutamate hypothesis of schizophrenia
Based on evidence showing hypofunction of glutamatergic signaling via NMDA receptors
Antagonists of NMDA subtype of glutamate receptor (phencylidine and ketamine) cause psychotic symptoms –> so lack of glutamate signaling may cause schizophrenia
This hypothesis does not negate the DA hypothesis since the two may be brought together by circuit-based models
Chemical classes of antipsychotic
Phenothiazines: chlorpromazine (Thorazine), thioridazine (Mellaril), fluphenazine (Prolixin)
Butyrophenones: haloperidol (Haldol)
Note: there are the typical antipsychotics
Metabolism of phenothiazine and butyrophenone
Absorption is variable and unpredictable
Highly lipid soluble and extensively protein bound
Complicated metabolic pathways with active metabolites (can last weeks!); plasma half life 10-20h; brain half lives longer
Usually administered once-daily
Pharmacologic activities of phenothiazines and haloperidol
Block DA, muscarinic cholinergic, alpha 1, histamine H1 receptors
Psychological effects: initial psychomotor slowing, emotional quieting (sedation and tranquilization), sleepiness, restlessness, emotional indifference (neuroleptic syndrome)
Brain electrical activity slowed with increased synchronization –> decrease seizure threshold and can elicit seizures in susceptible individuals
Inhibit vomiting by blocking D2 receptors in CTZ
Can produce hypothermia due to altered temperature regulation in hypothalamus
Clinical uses of typical antipsychotics
Schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder: acute treatment and prophylaxis of recurrence, does not cure but reduces symptoms, can take weeks or longer to see antipsychotic activity and in most cases not completely effective
Acute psychotic episodes: due to endocrine or metabolic disturbances or drug reactions; also used for adverse reactions to psychotomimetic drugs
Other psychiatric indications: acute treatment of manic episodes in bipolar affective disorder, psychotic depression, augmentation agent in depression, dementia (Alzheimers disease), rapid control of acute violence and agitation
Nonpsychiatric indications: Gilles De La Tourette’s Syndrome, nausea/vomiting (prochlorperazine, promethazine), intractable hiccough (?)
Note; NOT used for alcohol withdrawal or anxiety
Adverse reactions of typical antipsychotics
Behavioral: lethargy and drowsiness, pseudodepression, toxic confusional states (due to antimuscarinic activity)
Neurologic (extrapyramidal syndrome (EPS)) early onset: parkinsonian syndrome (sometimes goes away with time), akathisia (motor restlessness, not anxiety or agitation), acute dystonic reactions (abnormal contraction of muscle groups, concomitant sustained contraction of agonist and antagonist muscles including facial grimacing, torticollis, oculogyric crisis; is frightening and painful)
Neurologic (extrapyramidal syndrome (EPS)) late onset: tardive dyskinesia (develops after months or years on drug, may be irreversible) consists of lip smacking, chewing and tongue protrusions (bucco-linguo-masticatory syndrome), choreoathetoid limb movements; treatment is to gradually reduce dose but may make it worse
Endocrine: gynecomastia, galactorrhea, amenorrhea
CV: orthostatic hypotension, fainting with reflex tachycardia, cardiac toxicity due to local anesthetic effects
ANS: antimuscarinic effects (dry mouth, blurred vision, constipation, urinary retention), inhibition of ejaculation due to alpha 1 blockade
Weight gain
Pigmentary retinopathy (esp with thioridazine)
Allergic reactions: agranulocytosis, cholestatic (obstructive) jaundice, dermatitis and photosensitivity reactions
Neuroleptic malignant syndrome (NMS)
Rare idiosyncratic response caused by adverse reaction to medication with DA antagonist or by rapid withdrawal of DA medication
Fever, muscle rigidity, autonomic instability, altered mental status
Treatment: stop antipsychotic medication, cool, rehydrate, administer DA agonist and administer dantrolene (direct muscle relaxant)
Fatal (10-30%) but not when recognized early and treated aggressively (recovery 2-14 days)
Drug interactions with antipsychotics
Additive with other CNS depressants (sedative-hypnotics, antidepressants, antihistamines, opiates, ethanol)–however, OD is rarely fatal
Check for potential P450 interactions
Atypical antipsychotics
Clozapine (Clozaril), risperidone (Risperidal), olanzapine (Zyprexa), quetiapine (Seroquel), xiprasidone (Geodon), aripiprazole (Abilify)
Highly non-selective
Vary in antagonist activity at D1, D2, 5HT-1A, 5HT-2A, alpha 1, alpha 2, H1, histamine receptors (except aripiprazole is partial agonist at DA and 5HT!)
Psychological: sometimes effective in patients who have not responded to typical antipsychotics, more efficacious in treating negative symptoms of schizophrenia
Adverse effects of atypical antipsychotics
Neurologic (extrapyramidal): less likely to produce movement disorders and tardive dyskinesia
Endocrine: less likely to increase prolactin secretion; less likely to cause gynecomastia, galactorrhea and amenorrhea
CV: orthostatic hypotension, QT lengthening (Ziprasidon), increased risk of v-tach, torsades de pointes and sudden death (may all be due to interactions with other drugs metabolized by CYP3A4)
Weight gain
Atypical antipsychotics associated with development of T2DM!
Agranulocytosis (with Clozapine)
When may drugs be effective for schizophrenia?
For positive symptoms, secondary negative symptoms and behavioral disruption
