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Psychopharmacology > TASK 4 > Flashcards

TASK 4 Flashcards

1
Q

Schizophrenia

A

consists of positive symptoms (hallucinations and delusions) and negative symptoms (diminished emotional expression and lack of motivation), disorganized behavior, disturbed speech and cognitive deficits. Combinations of these symptoms must be present for at least 6 months

  • Onset: late adolescence to early adulthood
  • Prevalence: 0.5-1.0 % worldwide
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2
Q

Possible exogenous causes of schizophrenia

A
  • Maternal stress, maternal infections, nutritional deficiencies, pregnancy and birth complications
  • Socioeconomic factors: childhood poverty, other childhood adversities, immigration status
  • Marijuana: frequent users of marijuana
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3
Q

Neurochemistry and genetics of schizophrenia (causes)

A

The most frequently studied NTM in schizophrenia are dopamine and glutamate

  1. Stimulant drugs produce some symptoms similar to schizophrenia in normal individuals and exacerbate underlying symptoms similar to positive symptoms
  2. Drugs such as PCP and ketamine can also exacerbate positive symptoms in individuals who have schizophrenia
  3. Stimulants release dopamine and phencyclidine and ketamine antagonize NMDA (glutamate) receptors
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4
Q

Genetic involvement

A
  • Genetics: when one parent has the disorder, the probability of any child having the disorder Is 7%
    o Shares some common risk variants with other disorders such as MDD and ADHD

Genes that code for the dopamine receptor, such as the DRD2 gene, are involved in the pathophysiology of schizophrenia. Genes associated with the glutamate NTM system as well.
Major histocompatibility complex (MHC) – region of the genome containing genes associated with the body’s immune system also plays a role
- Within that complex, the risk of schizophrenia is most closely linked to the C4 gene: higher expressions of C4A lead to greater risk of schizophrenia (C4A is involved in pruning of synapses  too much pruning  cognitive deficits)

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5
Q

Serotonin and schizophrenia

A

LSD exert their psychedelic effect as agonist 5-HT2A receptors.
5-HT2 receptor antagonism might be responsible for some of the beneficial actions of antipsychotics
- May be involved in the improved neurological side effect profile of newer antipsychotics (because these drugs have lower potency for D2)

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6
Q

Mesolimbic dopamine pathway

A

Mesolimbic dopamine pathway: dopaminergic cells in the VTA to the nucleus accumbens in the ventral striatum

a) positive symptoms: The pathway is responsible for emotional behaviors, including positive symptoms of psychosis also important for motivation, pleasure and reward
- Drugs that increase dopamine will produce positive psychotic symptoms
- Hyperactivity in the mesolimbic pathway is also responsible for aggressive and hostile symptoms
- Probably caused by downstream consequence of dysfunction in the PFC and hippocampal glutamate activity.
b) reward and negative symptoms: antipsychotic treatment block D2 receptors in the mesolimbic pathway leading to a worsening of negative symptoms (loss of motivation and interest; anhedonia) and to a state of neurolepsis
- Inadequate reward mechanisms – drug abuse is likely because individuals attempt to boost the function of defective mesolimbic dopaminergic pleasure centers

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7
Q

Nigrostriatal dopamine pathway

A

substantia nigra via axons terminating in the striatum or basal ganglia. Part of extrapyramidal NS controlling motor movements

  • Deficiency of dopamine can cause movement disorders, including Parkinson’s disease and tardive dyskinesia
  • Deficiency in the basal ganglia produces akathisia, and dystonia
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8
Q

Mesocortical dopamine pathway

A

VTA to PFC
negative, cognitive and affective symptoms:
a) Branches of this pathway into the dorsolateral PFC are hypothesized to regulate cognition and executive functions
b) Branches into the ventromedial PFC are thought to regulate emotions and affect

Cognitive and some negative symptoms are believed to be caused by a deficiency of dopamine activity in this pathway (too less)

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9
Q

Tuberoinfundibular dopamine pathway

A

hypothalamus to anterior pituitary
Normally, these neurons are active and inhibit prolactin release.
- when D2 receptors are blocked by the drug, prolactin levels can rise, which is associated with galactorrhea, amenorrhea, and sexual dysfunctions

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10
Q

Thalamic dopamine pathway

A

Innervates the thalamus in primates. It arises from multiple sites. It may be involved in sleep and arousal
- no evidence for abnormal functioning of this dopamine pathway in schizophrenia

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11
Q

Problem of dopamine pathway hypothesis

A

Increasing dopamine in this pathway may improve the negative, cognitive and affective symptoms, but at the same time worsen the positive symptoms because dopamine in the mesolimbic pathway is already hyperactive.

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12
Q

Glutamate receptors

A

There are several types but they are always metabotropic glutamate receptors linked to G-proteins

Subtypes are grouped into 3 types:

  1. located postsynaptically to interact with other glutamate receptors to facilitate and strengthens the responses for glutamate
  2. presynaptically – autoreceptors to block glutamate release (drugs that stimulate these receptors, many therefore reduce glutamate release)
  3. “ (another type of them)

NMDA receptors:
responsible for long-term potentiation and synaptic plasticity. They are normally blocked by magnesium. In only opens to let calcium into the neuron when the following steps happen
1. Glutamate occupies the binding sites on the NMDA receptor
2. Glycine or D-serine binds to its side on the NMDA receptor
3. Depolarization occurs, allowing the magnesium plug to be removed

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13
Q

Cortico-brainstem glutamate projections

A

Projects from the cortical pyramidal neurons to brainstem NTM centers

  • including the raphe for serotonin, VTA and substantia nigra for dopamine, locus coeruleus for norepinephrine
    a) Glutamate neurons directly innervate monoamine neurons in brainstem to stimulate NTM release
    b) Indirect innervation of monoamine neurons by these excitatory cortico-glutamate neurons via GABA interneurons in the brainstem block NTM release
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14
Q

Cortico-striatal glutamate pathway

A

Projects from cortical pyramidal neurons to the striatal complex
It terminates on GABA neurons that project to the globus pallidus

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15
Q

Hippocampal-accumbens glutamate pathway

A

hippocampus to the nucleus accumbens. It terminates on GABA neurons that in turn project to the globus pallidus

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16
Q

Thalamo-cortical- glutamate pathway

A

Brings information from the thalamus back into the cortex, to process sensory information

17
Q

Cortico-thalamic glutamate pathway

A

Project directly back to the thalamus, where it directs the way in which neurons react to sensory information

18
Q

Cortico-cortical (direct) effects- and indirect pathway effects

A

Complex of many cortico-cortical glutamate pathways that are present within the cortex.
On the one hand, pyramidal neurons can excite each other within the cortex via direct synaptic input from their own NTM glutamate

On the other hand, one pyramidal neuron can inhibit another via indirect input, namely via the interneurons that release GABA

19
Q

NMDA hypofunction hypothesis

A

glutamate activity at NMDA receptors is hypofunctional due to abnormalities in the formation of glutaminergic NMDA synapses during neurodevelopment

Support:

a) PCP and ketamine are NMDA receptor antagonists, that make NMDA receptors hypofunctional, which induces a psychotic condition in normal humans very similar to symptoms of schizophrenia
b) PCP and ketamine also mimic the negative and affective symptoms

20
Q

How does NMDA hypo functioning hypothesis explain the dopamine hypothesis of schizophrenia?

A

Usually, glutamate is released from a cortical pyramidal neuron, which binds to an NMDA receptor of the GABAergic interneurons. GABA is then released and binds to GABA receptors on glutamate pyramidal neuron, which inhibits the pyramidal neuron and reduce the release of downstream glutamate

SCHIZOPHRENIA: GABA interneurons are not functioning correctly: cannot inhibit glutamate release, leading to an overactivity of glutamate

EFFECTS OF DOPAMINE PATHWAY:

1)
a) Cortico-brainstem glutamate neurons that innervate only the dopamine neurons projecting from the VTA to the nucleus accumbens in the mesolimbic dopamine pathway directly innervate those specific dopamine neurons and thus stimulate them
- hyperactivity of the mesolimbic dopamine neurons = positive symptoms of schizophrenia

b) hippocampus may contribute to hyperactivity:
I. defective hippocampal parvalbumin containing GABA interneuron going to
II. hippocampal glutamate neuron projecting to the nucleus accumbens, which projects two 2 different GABA spiny neurons
III. first GABA neuron going from nucleus accumbent to globes pallidus
IV. second GABA neuron going from globes pallid us to VTA
- first inhibition doesn’t work= excited, then inhibited by first spiny neuron = inhibited; then disinhibited by second spiny neuron = OVERACTIVE VTA = positive symptoms

2) cortico-brainstem glutamate neurons regulate the mesocortical dopamine pathway, which terminates in the VTA. they ndirectly innervate an inhibitory GABA interneuron, which innervates the mesocortical dopamine neuron. This leads to hypoactivity of mesocortical dopamine neurons
= negative, cognitive symptoms

21
Q

First generation antipsychotics/ typical or conventional antipsychotics

A

Most frequently used to treat schizophrenia.
- The response rate is 40-80%
All types are equally responsive in reducing positive symptoms

22
Q

Pharmacokinetics of first generation antipsychotics

A

lipid soluble, large volumes of distribution; oral absorption is unpredictable, and several FGAs undergo first-pass metabolism in the liver

  • Long half-lives: 20-40 hours
  • All FGAs are extensively metabolized by the liver and some have active metabolites
23
Q

PHARMACOLOGICAL EFFECTS of atypical antipsychotic drugs:

A

block of D2 receptors (therapeutic effects) but also blocks receptors of:

  • acetylcholine (dry mouth, dilated pupils, blurred vision, cognitive impairments, constipation, urinary retention tachycardia)
  • histamine (sedation, antiemetic effects)
  • serotonin (therapeutic efficacy, sedation, weight gain)
  • norepinephrine (hypotension and sedation)

Differing degrees of muscarinic cholinergic blockage may explain why some conventional antipsychotics have a lesser propensity to produce extrapyramidal effects:
dopamine normally inhibits acetylcholine release from cholinergic neurons, but if dopamine receptors are being blocked, ACh becomes overactive.
- drugs which also block ACh = less EPS

24
Q

other name for atypical antipsychotics

A

first generation antipsychotics or conventional antipsychotics

25
Q

Side effects of first generation antipsychotics

A

associated with histamine, acetylcholine, noradrenaline and dopamine blockade

Extrapyramidal symptoms

  • Dystonia: involuntary muscle contractions and sustained abnormal bizarre postures
  • Parkinsonian symptoms: resting tremor, rigidity (5-30 days after taking the drug)
  • Akathisia: feeling of anxiety, restlessness, pacing, purposeless action – common cause of nonadherence to treatment (subtle in onset – most difficult to treat)

Tardive dyskinesia: develops after a minimum of 6 months of treatment (20% of patients), but the risk of developing symptoms depends on dosage, neurological disorders, affective symptoms, gender and age
- Treatment options are limited

Neuroleptic malignant syndrome (NMS): occurs in response to increased dopamine transmission – fever, muscle rigidity, autonomic changes, altered consciousness and coma and mortality (20%)

Problems with FGA:

  • treatment resistance
  • no control of negative symptoms, even though positive symptoms are controlled
  • unable to tolerate side effects
26
Q

Second generation antipsychotics - pharmacological effect

A

Block dopamine D2 receptor but also 5-HT2 receptors (serotonin): the potency for serotonin receptors is greater than their potency at dopamine receptors - produce less neurobiological side effects

SGA are as effective as FGA

27
Q

Types of second generation antipsychotics

: Clozapine

A

: clinically superior to both typical and atypical antipsychotics, because it is effective in about one-third of patients who are resistant to conventional medications and because it lack extrapyramidal effect
- may reduce negative symptoms

  • Side effects: histamine antagonism (drowsiness), adrenergic antagonism (dizziness and decreased blood pressure), anticholinergic= drowsy hyper salivation
  • agranulocytosis: degeneration of white blood cells that must be monitored, otherwise lethal

Least prescribed due to worst side effects

28
Q

Types of second generation antipsychotics: Risperiodne

A

Half life: 23 hours of active intermediate

Side effects: extrapyramidal symptoms, menstrual abnormalities, infertility, changes in libido…

FIRST line drug when wanting to treat negative symptoms in the first episode
- used to treat bipolar, autism and borderline

29
Q

Types of second generation antipsychotics: Olanzapine

A

like clozapine, highly sedating and anticholinergic
Side effects:
- drug reaction with eosinophilia and systemic symptoms (DRESS)- fever, swollen lymph nodes and face, can result in injury to organs, and mortality
- Post injection delirium/sedation syndrome (PDSS): intense sedation that can lead to ataxia and abrupt onset of sleep (only when injected)
- No risk for agranulocytosis

30
Q

Types of second generation antipsychotics: Quentiapine

A

reduce positive symptoms and little EPSP

Side effects: sedation, postural hypotension, increase in QTc interval (increase risk of potentially fatal ventricular arrhythmia)

31
Q

Types of second generation antipsychotics: Apriprazole

A

first ‘third generation’ antipsychotic drug: It is a partial agonist at D2 and 5HT1A receptors as well as an antagonist at 5-HT2 receptors

  • Meant to stabilize the dopamine system because it has lower intrinsic activity – less efficacy in producing changes in dopamine levels: will decrease dopamine levels that are too high while increasing dopamine levels that are too low
  • Positive effects on the negative symptoms as well
  • Anxiolytic and antidepressant action
  • low risk of EPS, tar dive dyskinesia

Side effect: nausea, tremor, insomnia, headache, most likely to produce akathisia, and increase risk fo pathological gambling and compulsive behaviors

32
Q

Types of second generation antipsychotics: Asenapine

A

approved for the treatment of schizophrenia and bipolar disorder. It has to be dissolved under the tongue to be absorbed effectively
Side effects: dopaminergic side effects

33
Q

Types of second generation antipsychotics: Cariprazine

A

partial agonist at both D3 and D2 receptors – potency is greater for D3 receptors
Side effects: somnolence, vomiting, EPS akathisia

34
Q

Other treatment investigations

A

nicotinic acetylcholine receptor: Stimulation of nicotinic receptors is thought to be related to enhanced cognitive functions

Glutamate system: Regulating glutamate is expected to reduce the positive symptoms

Serotonin system:
5HT6 receptor antagonist thought to increase glutamate and cholinergic transmission and elevated dopamine and norepinephrine in the PFC
Blockage of 5HT2A receptor is thought to improve negative symptoms

PDE: Inhibitors of the PDE enzyme system lead to cognitive improvement in animal models

35
Q

CATIE study

A

AIM: to report the primary outcomes of a double-blind, active-control clinical trial designed to compare the effectiveness of atypical and conventional antipsychotic drugs

METHOD: Patients were randomly assigned to receive olanzapine, perphenazine (only FGA), quetiapine, or risperidone under double-blind conditions followed for up to 18 months until the treatment was discontinued
- Ziprasidone was approved and added to the study in January 2002

a) Primary outcome measure: discontinuation of treatment for any cause (judgement of efficacy, safety, and tolerability into a global measure of effectiveness)
b) Secondary outcome: reason for the discontinuation of treatment; scores on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions (CGI) Scale

RESULTS:

  1. Only a minority of patients continued their medication for the duration of rate one (discontinuation rates (62-82%) - indicate limitations of effectiveness and tolerability (no differences between the groups in discontinuation of treatment due to side effects)
    - earlier time to discontinuation: higher baseline PANSS score, longer duration since the first use of antipsychotic medication, and antipsychotic drug taken before the study
  2. Olanzapine had the lowest rate of discontinuation and showed the greatest effect in reducing psychopathology, longer duration of successful treatment and lower rates of hospitalizations for an exacerbation of schizophrenia
  3. Results of other SGA similar to perphenazine
  4. Dose could be a factor in the performance of the various agents studied (low dose of perphenazine appears to have diminished the frequency of extrapyramidal side effects in patients who received the first-generation drug BUT the proportion of patients with EPS did not differ among the 2 conditions )
    - Still, most patients discontinued perphenazine compared to the other medication due to EPS

Psychopharmacology (4 decks)

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