Stahl Psychosis, Schizophrenia Chapters 4

Passing Grades Flashcards

Psychosis definition: delusions, hallucinations, disorganized speech/behaviors, and gross distortions of reality p.79

presence of psychosis as a Defining feature of the diagnosis

1. schizophrenia,
2. substance-induced psychotic disorders,
3. schizophreniform,
4. schizoaffective
5. delusional disorder,
6. brief psychotic disorder, and
7. psychotic disorder due to a general medical condition p.79

disorders that may or may not have psychotic symptoms as Associated features

1. mania
2. depression
3. cognitive disorder, e.g. Alzheimer's Disease p.79

perceptual distortions
hallucinations p.79

motor disturbances
immobile & rigid; hyperactive and overly excited p.80

paranoid psychosis
paranoid projections, hostile belligerence, and grandiose expansiveness p.80

disorganized/excited psychosis
conceptual disorganization, disorientation, excitement p.80

depressive psychosis
retardation and apathy
anxious self-punishment and blame p.80

Affects 1% of the population
schizophrenia p.80

schizophrenia by Definition
Disturbance that must last 6 months or longer, including at least:
1 month of delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms p.81

25%-50% of schizophrenic patients attempt suicide, and
10% successfully commit suicide p.80

positive symptoms of schizophrenia

1. delusions
2. hallucinations
3. distortions/exaggeration in language and communication
4. disorganized speech
5. disorganized behaviors
6. catatonic behavior
7. agitation p.81

negative symptoms of schizophrenia
alogia, affective blunting, asociality, anhedonia, avolition p.81–82

psychosocial interventions along with antipsychotics can be helpful to
reduce negative symptoms p.83

observable negative symptoms
reduced speech, poor grooming, limited eye contact p.84

negative symptoms identified with questions
reduced emotional responsiveness, reduced interest, reduced social drive p.84

5 Dimensions of schizophrenia

1. positive symptoms
2. negative symptoms
3. cognitive symptoms
4. aggressive symptoms
5. affective symptoms p.83–84

mesolimbic pathway type of Symptoms
positive symptoms, too much dopamine p.89–90

mesocortical/prefrontal cortex and nucleus accumbens type of Symptoms
negative symptoms, too little dopamine p.85

ventromedial prefrontal cortex type of Symptoms
affective symptoms, too little dopamine p.85

dorsolateral prefrontal cortex type of Symptoms
cognitive symptoms, too little dopamine p.85

orbitofrontal cortex (OFC) and amygdala type of Symptoms
aggressive and impulsive symptoms, too little dopamine p.85

precursor of Dopamine
Tyrosine (TYR) p.86

Synthesis of DA

1. tyrosine pumps tyrosine (TYR) in the dopamine nerve terminal
2. tyrosine hydroxylase (TOH) converts tyrosine to DOPA
3. DOPA decarboxylase (DDC) converts DOPA to DA
4. DA stored in VMAT2 until release in the synapse during neurotransmission p.86

TYR
Tyrosine p.86

TOH
tyrosine hydroxylase p.86

DDC
DOPA decarboxylase p.86

DA neuron uses
reuptake presynaptic transporter DAT p.86

DAT exists
presynaptically and is responsible for clearing out excess DA in the synapse

DATS are not present in
high density at the axon terminals of all DA neurons p.86

In the prefrontal cortex, DATS are
sparse and are inactivated by MAOa, MAOb, or catechol-O-methyl-transferase (COMT), and can also be transported by the “false” substrate NET p.86

DA =

1. DAT brings DA into the presynaptic nerve
2. DA is stored in the VMAT2 for further use p.87

VMAT2 takes DA
up into the synaptic vesicles for future neurotransmission p.87

Presynaptic D2 autoreceptors
are like gatekeepers and regulate release or no release of DA from the presynaptic neuron p.88

If DA binds to the presynaptic D2 autoreceptor
will block DA from being released p.88

If no DA is bound to the presynaptic D2 autoreceptor
will open a molecular gate to allow DA release p.88

location of presynaptic D2 autoreceptors
axon terminal or on the somatodendritic area p.89

POSTSYNAPTIC receptors – D1, D2, D3, D4, D5 – which is best understood?
postsynaptic receptor D2 p.87

DATs are sparse in the
Prefrontal cortex p.86

Excess DA can be terminated via
MAOA, MAOB, COMT, as well as transported away via NETs as a false substrate p.87

COMT breaks down DA
extracellularly p.87

MAOA or MAOB breaks down DA
intracellularly p.97

mesolimbic dopamine pathway =
Group of dopaminergic axons that originates in the Ventral Tegmental Area and travels to structures of the limbic system, including the nucleus accumbens, septum, amygdala, and hippocampus. Important role in motivation, pleasure, and reward p.89

mesolimbic dopamine hypothesis of positive symptoms of schizophrenia
modern designation p.90

cocaine, amphetamine, stimulants releases
dopamine, and if repetitively taken can cause positive symptoms of schizophrenia p.90

all antipsychotics that treat Positive symptoms
Block the dopamine D2 receptor (antagonist) p.90

mesocortical dopamine pathway projects
from ventral tegmental area but sends its axons to the prefrontal cortex where they may have a role in mediating cognitive symptoms (DLPFC) and affective symptoms (VMPFC) via hypoactivity in these pathways p.91
and negative symptoms p.92

mesocortical dopamine projections resulting in negative symptoms may be a result of
neurodevelopment abnormalities in the NMDA (N-methyl-D-aspartate) glutamate system p.92

nigrostriatal dopamine pathway projects
from substantia nigra to striatum, is part of the extrapyramidal nervous system and controls motor function and movement p.95

hyperactivity of DA in the nigrostriatal pathway
hyperkinetic movement disorders, chorea, dyskinesias, and tics p.95

deficiency of DA in the nigrostriatal pathway results in
movement disorders, Parkinson's disease, rigidity, akinesia/bradykinesia, and tremor p.95

deficiency of DA in the basal ganglia results in
akathisia (a type of restlessness), and dystonia (twisting movements especially of the face and neck) p.95

tuberoinfundibular dopamine pathway projects
from the hypothalamus to the anterior pituitary gland and controls prolactin secretion p.95

too much DA in the tuberoinfundibular dopamine pathway results in
increased prolactin levels, resulting in galactorrhea, amenorrhea, and sexual dysfunction p.95

DA is normal in which pathways in untreated schizophrenia
tuberoinfundibular and nigrostriatal pathways p.95

Thalamic dopamine pathway
Recently, a dopamine pathway that innervates the thalamus in primates has been described. It arises from multiple sites, including the periaqueductal gray matter, the ventral mesencephalon, various hypothalamic nuclei, and the lateral parabrachial nucleus. Its function is still under investigation, but it may be involved in sleep and arousal mechanisms by gating information passing through the thalamus to the cortex and other brain areas. There is no evidence at this point for abnormal functioning of this dopamine pathway in schizophrenia. p.96

Glutamate synthesis

1. Glutamate released from the presynaptic neuron
2. Taken up into glial cells via EAAT
3. glutamine synthetase converts glutamate into glutamine
4. glutamine is transported out of the glial cell by Specific Neutral Amino Acid Transporter (SNAT) by reverse transport
5. then taken up by SNATs on glutamate neurons
6. glutaminase converts glutamine into glutamate
7. then taken back into the synaptic vesicle by VGluT, where it is stored p.97–98

glutamine synthetase converts
glutamate into glutamine

glutamine is transported out of the _________ cell by _________
Glial; specific neutral amino acid transporter (SNAT)

Glutaminase converts _____ to glutamate
glutamine

The NMDA receptor for Glutamate requires a
co-transmitter to function p.96

Co-transmitters for glutamate are either
amino acid glycine or D-serine p.99

Selective Glycine Reuptake Inhibitors (SGRIs) are being tested
to boost glycine action, and then glutamate action at the NMDA receptors p.100–101

metabotropic receptors are
associated with G proteins p.101

number of metabotropic glutamate receptors
eight subtypes, organized into three separate groups p.101

Groups II and III metabotropic receptors can
occur presynaptically, where they function as autoreceptors to block glutamate release p.101

drugs that stimulate presynaptic autoreceptors as agonists may =
REDUCE glutamate release, thereby be useful as anticonvulsants and mood stabilizers, and protect against glutamate excitotoxicity p.101

Group I metabotropic glutamate receptors are
mGluR1, mGluR5 p.103

Group II metabotropic glutamate receptors are
mGluR2, mGluR3 p.103

Group III metabotropic glutamate receptors are
mGluR4, mGluR6, mGluR7, mGluR8 p.103

Group I metabotropic receptors are located
predominately postsynaptically, and strengthen responses mediated by ligand-gated ion-channel receptors for glutamate p.103

Glutamate receptors are
Metabotropic Groups I, II, III and AMPA, Kainate, NMDA p.103

NMDA, AMPA, and kainate receptors for glutamate are members of the
ligand-gated ion-channel family of receptors, also known as ionotropic or ion-channel-linked receptors p.103

AMPA ionotropic (ligand-gated ion channel) receptors gene family are
GluR1, GluR2, GluR3, GluR4 and tend to be postsynaptic p.103

Kainate ionotropic (ligand-gated ion channel) receptors gene family are
GluR5, GluR6, GluR7, KA1, KA2 and tend to be postsynaptic p.103

NMDA ionotropic (ligand-gated ion channel) receptors gene family are
NR1, NR2A, NR2B, NR2C, NR2D and tend to be postsynaptic p.103

specifically, AMPA and kainate receptors may mediate
fast, excitatory neurotransmission, allow sodium to enter the neuron to depolarize it p.101

NMDA receptors in the resting state normally are blocked by
magnesium, which plugs the calcium channel; in order to open the channel:

1. glutamate and glycine must bind to different sites on the receptor
2. depolarization must remove the magnesium while glutamate and glycine are bound to their sites on the ligand-gated ion channel p.101

magnesium is a negative allosteric modulator (NAM)
at NMDA glutamate receptors p.101

Glutamatergic pathways are

1. cortico-brainstem
2. cortico-striatal
3. hippocampal-striatal
4. thalamo-cortical
5. cortico-thalamic
6. cortico-cortical (direct)
7. cortico-cortical (indirect) p.102–103

cortico-brainstem glutamate pathway projects =
from cortical pyramidal neurons to the brainstem neurotransmitter centers:

1. raphe for serotonin
2. ventral tegmental area and substantia nigra for dopamine
3. locus coeruleus for norepinephrine p.103

direct innervation of monoamine neurons in the brainstem by these excitatory cortico-brainstem glutamate neurons
stimulates neurotransmitter release p.103

indirect innervation of monoamine neurons by these excitatory cortico-brainstem glutamate neurons via GABA interneurons in the brainstem
blocks neurotransmitter release p.103

D2 antagonists can induce
Extrapyramidal symptoms

D2 antagonists reduce
Positive symptoms of schizophrenia

Dopamine pathways in the brain
Mesolimbic, mesocortical, nigrostriatal, tuberoinfundibular pathway

Blockage of NMDA receptors
may block the excitatory actions of glutamate

NMDA receptor hypofunctional hypothesis is based on that
PCP is a NMDA receptor antagonist; induces positive, affective, negative, and cognitive symptoms

Stress-Diathesis Model
susceptible genes (nature) and epigenetic stressors may result in schizophrenia

functional magnetic resonance imaging (fMRI)
A noninvasive imaging technique that uses magnetic fields to map brain activity by measuring changes in blood flow and oxygen levels

patient calculating a math problem would over- or under-light the ______ with the fMRI
dorsolateral prefrontal cortex (DLPFC)

patient looking at a sad face or something emotional would either over- or under-light the ______ and ______ with the fMRI
ventromedial prefrontal cortex (VMPFC); amygdala

Dysbindin
Axonal protein involved in synapse formation, especially in the hippocampus of the limbic system

Neuregulin

1. involved in neuronal migration, glial cell genesis, and myelination
2. activates an ErbB4 signaling system co-localized with NMDA receptors

ErB4 receptors interact with
the postsynaptic density of glutamate synapses and may mediate neuroplasticity triggered by NMDA receptors

DISC1 gene
a disrupted gene linked to schizophrenia; involved in neurogenesis, neuronal migration, dendritic organization; affects transport of synaptic vesicles into presynaptic glutamate terminals and regulates cAMP signaling, influencing glutamate neurotransmission via metabotropic glutamate receptors

long-term potentiation
an increase in a synapse's firing potential after brief, rapid stimulation; believed to underlie learning and memory; occurs when glutamate synapses are active and NMDA receptors trigger an electrical phenomenon

dysbindin, DISC1, and neuregulin, and ______ leads to structural and functional changes of the synapse that make neurotransmission more efficient, and sometimes called ____________ of synapses. This includes increasing the number of ____________ receptors
Long-term potentiation (LTP); strengthening; AMPA

AMPA receptor
are important for mediating excitatory neurotransmission and depolarization at glutamate synapses

Stimulation of 5HT1A receptors increases
DA release

Stimulation of 5HT2A receptors
inhibits DA release

5HT can regulate DA release
directly or indirectly

when 5HT acts on 5HT2A receptors on a DA neuron, what happens
causes a reduction in DA release because 5HT2A receptors are inhibitory

when 5HT acts on 5HT1A receptors on a DA neuron what happens
5HT inhibits its own release; the reduction of 5HT causes disinhibition of DA release → increased DA output

blocking (antagonists) 5HT2A receptors on postsynaptic DA neurons or on GABA interneurons should result in an
increased DA release

stimulation of 5HT2A receptors located on glutamate cell bodies induces
an increase in glutamate release

stimulation of 5HT1A receptors located on glutamate cell bodies
inhibits glutamate release