Week 3 (Vision and Psychosis)

Question 1

Exposure and symptoms of PTSD

Answer 1

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)

Question 2

Brain regions involved in PTSD

Answer 2

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

Question 3

Amygdala functions

Answer 3

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

Question 4

Hippocampus and medial temporal lobe functions

Answer 4

Formation of new memories

Spatial navigation

Stress response and feedback regulation of glucocorticoid secretion

Question 5

What does PTSD ultimately lead to?

Answer 5

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

Question 6

Activity of medial prefrontal cortex (mPFC) in PTSD

Answer 6

Medial prefrontal cortex usually inhibits the amygdala

In PTSD, mPFC does not inhibit amygdala, so the amygdala is over-active

Question 7

Interoceptive vs. exteroceptive stimuli

Answer 7

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)

Question 8

Neurochemical changes in PTSD

Answer 8

NE increased –> increased BP, HR, etc

5HT dysregulated

Question 9

Modification of memories

Answer 9

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)

Question 10

What determines whether someone develops PTSD

Answer 10

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

Question 11

Complex PTSD

Answer 11

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

Question 12

Acute stress disorder

Answer 12

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

Question 13

Observations about the development of PTSD after traumatic event

Answer 13

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

Question 14

Pharmacological treatment for PTSD

Answer 14

Mostly symptomatic

Beta blockers

SRIs for anxiety, phobias, PTSD

Benzos acutely (not long-term!)

Question 15

Psychotherapy for PTSD

Answer 15

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

Question 16

Continuum of CNS stimulant action

Answer 16

Increased alertness

Nervousness and anxiety

Stimulation of respiration and cardiovascular function

Convulsions and death

Question 17

Glycine

Answer 17

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

Question 18

Strychnine

Answer 18

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)

Question 19

General effects of psychomotor stimulants

Answer 19

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

Question 20

Methylxanthines

Answer 20

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

Question 21

Caffeine

Answer 21

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

Question 22

Pharmacologic effects of caffeine

Answer 22

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

Question 23

Adverse effects of caffeine

Answer 23

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

Question 24

Clinical uses of caffeine

Answer 24

Headache, migraine (vasoconstrictive actions)

Formerly treatment for asthma (theophylline) but not anymore because inhaled corticosteroids more effective

Relative potencies: theophylline > caffeine > theobromine

Question 25

Controlled substances

Answer 25

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)

Question 26

Amphetamines

Answer 26

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

Question 27

Ephedrine, pseudoephedrine (mixed)

Answer 27

Indirectly acting sympathomimetics

Alpha and beta adrenergic agonists AND block reuptake of NE, DA

Ephedrine more potent than pseudoephedrine

Question 28

Methamphetamine

Answer 28

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)

Question 29

Adverse reactions of amphetamines

Answer 29

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

Question 30

Drugs to treat ADHD

Answer 30

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

Question 31

Methylphenidate

Answer 31

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

Question 32

Appetite suppressants

Answer 32

Phentermine: amphetamine analog but less potent

Topiramate + phentermine combination (Qsymia)

Question 33

Modafinil (Provigil)

Answer 33

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

Question 34

Cocaine

Answer 34

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

Question 35

Pharmacologic effects of cocaine

Answer 35

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

Question 36

Adverse effects of cocaine

Answer 36

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

Question 37

Cocaine abuse

Answer 37

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

Question 38

MDMA (ecstasy)

Answer 38

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)

Question 39

Adverse effects of MDMA

Answer 39

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)

Question 40

“Bath salts”

Answer 40

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

Question 41

Hallucinogens

Answer 41

LSD

Psilocybin

Mescaline

Question 42

LSD (lysergic acid diethylamide)

Answer 42

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

Question 43

Stimulant-psychosis

Answer 43

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

Question 44

Psychosis

Answer 44

Generic term that describes some impairment in “reality testing” resulting in the inability to distinguish reality from fantasy

Question 45

Hallucination vs. illusion

Answer 45

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

Question 46

Auditory verbal hallucinations

Answer 46

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

Question 47

How auditory verbal hallucinations may be formed?

Answer 47

Inner speech, memories, thoughts may be excessive, negative or otherwise abnormal –> errors in processing –> non-volitional, non-self, auditory, external

Question 48

What must hallucinations be differentiated from?

Answer 48

Normal thoughts, inneer speech = verbal thinking

Ruminations, obsessions = self, but ego-dystonic

Thought insertion, illusions = non-self

Question 49

Delusions

Answer 49

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)

Question 50

Themes of delusions

Answer 50

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)

Question 51

Cognitive features of delusions

Answer 51

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

Question 52

Psychosis and dopamine

Answer 52

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

Question 53

DDx of hallucinations and/or delusions (aka psychosis)

Answer 53

No mental illness

Malingering

Mania

Major depressive episode

Dementia

Delirium

Non-psychiatric brain disorder (seizure, tumor, infection, endocrine, etc)

Question 54

Drug-induced psychosis

Answer 54

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)

Question 55

Symptomatic domains in schizophrenia

Answer 55

Positive

Negative: affective flattening, alogia, avolition-apathy, anhedonia-asociality

Disorganized: tangential, circumstantial, loosening of associations

Question 56

Disorganization

Answer 56

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”)

Question 57

Negative symptoms

Answer 57

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

Question 58

Primary vs. secondary negative symptoms

Answer 58

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

Question 59

DSM-IV Criterion A

Answer 59

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

Question 60

Primary brain/CNS tumors

Answer 60

Meningioma (30%)

Glioblastoma (20%)

Pituitary adenoma (6-20%)

Question 61

Intra-axial vs. extra-axial tumors

Answer 61

Intra-axial (brain parenchyma): glioblastoma

Extra-axial (not brain parenchyma): meningioma

Question 62

Brain tumors in children

Answer 62

Pliocytic astrocytoma (cerebellum)

Medulloblastoma (cerebellum)

Craniopharyngiomas (suprasellar)

Germinoma (pineal gland/hypothalamus)

Pituitary adenomas

Other gliomas

Question 63

Neurofibromatosis Type 2 (NF 2)

Answer 63

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

Question 64

Meningiomas

Answer 64

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

Question 65

Common secondary (metastatic) brain tumors

Answer 65

Lung, breast, renal, melanoma, GI (colon)

Carcinomas are epithelial and therefore express keratin in contrast to GBMs which are GFAP+

Question 66

How are biomarkers used for brain tumors?

Answer 66

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

Question 67

IDH mutation

Answer 67

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

Question 68

Glioblastoma

Answer 68

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

Question 69

Epidemiology of schizophrenia

Answer 69

<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

Question 70

Genetics of schizophrenia

Answer 70

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)

Question 71

Brain abnormalities associated with schizophrenia

Answer 71

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

Question 72

Age of onset of schizophrenia

Answer 72

Males: 20-24

Females: 25-29

Question 73

Course of schizophrenia

Answer 73

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

Question 74

Schizophreniform and brief psychotic disorder

Answer 74

NOT schizophrenia because not for 6 months

Schizophreniform < 6 months

Brief psychotic disorder < 1 month

Question 75

Favorable predictors of overall course of schizophrenia

Answer 75

Acute onset

Later onset

Onset with precipitating event

Good premorbid functioning

Lack of negative and cognitive symptoms

Female

Mood symptoms

Psychosocial support

Question 76

Specific cognitive symptoms of schizophrenia

Answer 76

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)

Question 77

Effect of cognitive impairment on schizophrenics

Answer 77

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

Question 78

Initial workup when schizophrenia is suspected

Answer 78

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

Question 79

Antipsychotic medications for schizophrenia

Answer 79

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

Question 80

Response to antipsychotic treatment in schizophrenics

Answer 80

“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

Question 81

Outcomes of pharmacological treatment for schizophrenia

Answer 81

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

Question 82

Psychotherapy for schizophrenia

Answer 82

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

Question 83

Delusional disorder

Answer 83

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

Question 84

Schizoaffective disorder

Answer 84

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

Question 85

Cluster A personality disorders

Answer 85

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

Question 86

Chlorpromazine

Answer 86

First antipsychotic drug (made in 1950s)

Question 87

Phenothiazines

Answer 87

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)

Question 88

Positive and negative symptoms of psychotic disorders

Answer 88

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)

Question 89

Dopamine hypothesis of schizophrenia

Answer 89

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

Question 90

5 dopamine receptor subtypes

Answer 90

D1 and D5 receptors increase adenylyl cyclase activity

D2, 3, 4 receptors inhibit adenylyl cyclase activity

Question 91

What determines the clinical potency of most antipsychotic drugs?

Answer 91

Ability to bind to D2 receptor (NOT ability to bind D1 receptor)

Question 92

Serotonin hypothesis of schizophrenia

Answer 92

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

Question 93

Glutamate hypothesis of schizophrenia

Answer 93

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

Question 94

Chemical classes of antipsychotic

Answer 94

Phenothiazines: chlorpromazine (Thorazine), thioridazine (Mellaril), fluphenazine (Prolixin)

Butyrophenones: haloperidol (Haldol)

Note: there are the typical antipsychotics

Question 95

Metabolism of phenothiazine and butyrophenone

Answer 95

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

Question 96

Pharmacologic activities of phenothiazines and haloperidol

Answer 96

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

Question 97

Clinical uses of typical antipsychotics

Answer 97

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

Question 98

Adverse reactions of typical antipsychotics

Answer 98

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

Question 99

Neuroleptic malignant syndrome (NMS)

Answer 99

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)

Question 100

Drug interactions with antipsychotics

Answer 100

Additive with other CNS depressants (sedative-hypnotics, antidepressants, antihistamines, opiates, ethanol)–however, OD is rarely fatal

Check for potential P450 interactions

Question 101

Atypical antipsychotics

Answer 101

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

Question 102

Adverse effects of atypical antipsychotics

Answer 102

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)

Question 103

When may drugs be effective for schizophrenia?

Answer 103

For positive symptoms, secondary negative symptoms and behavioral disruption