Schizophrenia - pathophys and treatment Flashcards
What are the important second generation antipsychotic drugs and what how are they different than the first generation ones?
• Clozapine is the poster child of the second generation antipsychotics
○ Also risperidone
○ Olanzapine
○ Quetiapine
○ Asenapine
○ Ziprasidone
§ All try and mimic clozapine and block of 5Ht-2 receptors
• Also called an atypical neuroleptic
• Has antidopaminergic activity, but did not cause as much parkinsons symptoms as expected
• Called atypical because of reduced risk for induced parkinsonism
• Seems to be more effective than other neuroleptics for 30% of patients
• Under strict observation still for tendency to participate in agranulocytosis (white blood cell production problems)
What’s the principle advantage of the atypical neuroleptics?
• Reduced parkinsonism
• However, they do have increased weight gain, hypercholesterolemia and DM associated with them
○ Ehanced appetite in many patients
What are the most important first generation antipsychotic drugs?
• Chlorpromazine is the first one
• After that success 19 mimics were made, all dopamine blockade
• Three basic types
○ Phenothiazines
○ Thioxanthines
○ Butyrophenones
• Highly lipophilic, slowly eliminated (days 1/2 lives)
• No tolerance build to therapeutic effects
What, after a very long time with first gen neuorleptic treatment, can happen to movement systems?
- There can be restructureing of the caudate and putamen (increase DA receptors)
- Result is tardive dyskinesia
What are the important butyrophenones?
*(haloperidol)
What are the important thioxanthines?
• Thiothixine
What are the important phenothiazines?
- Chlorpormazine
* Perphenazine
What is the dopaminergic mechanism of antipsychotic drugs?
• All antipsychotics can produce parkinsonism. Thus all of them deal with DA systems
• Compete with DA for post-synaptic receptors on many neurons.
• Five DA receptors (DR1-5) are involved
• DR2 is on postsynaptic synapses on many neurons, including the DA neurons themselves where it acts as a modulator of dopamine release
• The most senstive to antipsychotics is DR2
• Full basis of therapeutic effect is unknonw, but DR2 receptor activation causes neurons to be more senstive to sensory inputs
○ Compounding patient’s problems with information process and sensory gating (more under stress)
While schizophrenia was once the ‘graveyard of neuropathologists’, there are more recent discoveries that have helped compile some better pathology-related understanding of the disease. What are these discoveries?
• Evidence for inhibitory interneuron deficits
○ Both number and expression of various peptides and proteins
○ AND their migration from cortical subplate
• Ultrastructural studies of synaptic proteins in postmortem human brains demonstrate reduced synapse number in the frontal cortex, hippocampus and basal ganglia
• Also detected altered dendritic numbers in schizophrenia, suggesting failure to develop normal synaptic connections by both pyramidal and inhibitory neurons.
• MRI shows consistent evidence of enlarged ventricles and diminished volume in several regions, including the hippocampus and the superior temporal cortex
• NEGATIVE signs of gliosis and inflammation
How is the thalamus involved in psychotic illness?
• The thalamus is the gateway to cortical processing for all incoming sensory information
○ Somatosensory
○ Auditory
○ Visual
• Two abnormalities of thalamic function have been proposed in schizophrenia
• First, a decrease in the total thalamic volume might signify a breakdown of its sensory filtering abilitites
○ Leads to increased stimulation of primary sensory cortical areas
• Second, dysfunction of the medial dorsal nucleus of the thalamus leads to impairments of cortical association areas, especially the dorsal lateral prefontal cortex
How is the medial temporal lobe involved in psychotic illness?
• Medial temporal lobe has two major functions
○ Integrate multimodal sensory information for storage and retrieval of memory
○ Attach limbic valence to sensory information
• In schizophrenia, mild cortical atrophy has been reported in the medial temporal lobe
• Focal abnormalities indicating abnormal alignment of neurons have been observed in medial temporal lobe structures such as the amygdala, entorhinal cortex and hippocampus
How is the hippocampus involved in psychotic illness?
• There is also evidence of hippocampal dysfunction in the pathogenesis of schizophrenia
○ Serial circuity of glutamatergic pyramidal and nonpyramidal neurons provides the structural basis for the formation of long term membories
○ The hippocampus is also closely connected with the limbic system
○ Hippocampal formation is recruited via these connections to regulate emotion or to modulate information with respoect to emotions
§ Most studies have found no change in the number of hippocampal pyramidal neurons
§ But nonpyramidal cells in the hippocampus seem to be reduced
§ Synaptic architecture also seems to be changed, suggesting altered plasticity
§ Blood flow and metabolism is increased at baseline
§ Noticeably increased during positive symptom of psychosis
Describe the layout of the association cortex (layers)
- 6 layer isocortex
- Layers 2 and 4 are defined by a high density of interneurons
- 3 and 5 are defined by a high density of pyramidal cells that collect input through their dendrites and project to other cortical or subcortical areas
- Interneurons are GABA
- Pyramidal cellsa re gulatmate
What is going on with the association cortex in schizophrenia?
- Volume reduction of the association cortex has been reported
- rCBF and glucose metablosim are abnormal in the frontal cortex at rest and during the performance of cognitive tasks
- Patients can exhibit hypofrontality (not even being able to activate prefrontal cortex)
- DLPFC (dorsolateral pre-frontal cortex) is actually HYPERactive, indicating inefficiency
What does the dopamine theory of psychosis say?
- Psychosis is caused by dysregulation of dopamine in the brain
- Involved mesolimbic system and mesocortical system
What does the mesocortical system have to do with psychosis?
• Mesocortical system is composed of DA neurons from VTA and the substantia nigra
• VTA neurons included in the mesocortical system release dopamine to the prefrontal cortex and regulate areas involved in cognitive processing
○ One example being dorsal lateral prefrontal cortex for executive function
• This is the system associated with negative symptoms of schizoprenia
What do the mesolimbic and mesocortical systems have to do with psychosis?
- Mesolimbic system is composed of the dopamine neurons from the ventral tegmental area (VTA)
- Release dopamine to the nucleus accumbens
- Regulates reward pathways and emotional processes and is associated with the positive symptoms of schizophrenia
What are the NT systems that play a role in the pathogenesis of schizophrenia?
- Dopamine, serotonin and glutamate
* These are the targets for the various antipsychotic drugs
The earliest, and perhaps the most pharmacologically supported, theory for schizophrenia’s major NT pathway is what?
• Dopamine theory
• First antipsychotics developed deal with DA release pathways
• (postulates) The abnormality in brain fucntin in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in the mesolimbic pathway
• Support -
○ Effective antipsychotics block CNS dopamine receptors (postsynaptic D2)
○ Drugs that increase DA activity can aggravate/produce schizophrenia
○ Post-mortem studies showing increased striatal dopamine synthesis and release and receptors (indicating overactive NT system)
Describe the major brain DA pathways.
- 1 - from the tegmentum to the nucleus accumbens (mesolimbic)
- 2 - from the tegmentum to the cortex (mesocortical)
- 3 - from the substantia nigra to the striatum (nigrostriatal)
- 4 - from the hypothalamus and out (tuberinfundibular)
Describe the mesolimbic pathway and the drugs used to modulate it.
- Limbic structures are thought to subserve the integration of sensory input and motor responses with affective or emotional data.
- Hyperactivity here is believed to contribute to the positive symptoms of schizophrenia
- Drugs - D2 receptor block - antipsychotic agents (all)
Describe the mesocortical pathway and the drugs used to modulate it
• Cortical structures (DLPFC, VMPFC) are involved in communication and social abilities
• Hypoactivity due to cell loss in the prefrontal cortex contributes to the negative symptoms of schizophrenia
○ Poverty of speech, anhedonia, lack of motivation, social isolation
• Drugs - negative symptoms don’t respond well to D2 receptor blockade
• Respond better to atypical antipsychotics like clozapine or olanzapine
• These block 5HT2A receptors
Describe the nigrostriatal pathway and the drugs used to modulate it
• Part of a larger subcortical circuit known as the basal ganglia
• Plays a central role in planned, coordinated movement
○ Dysregulated in parkinsons
• Drugs - antipsychotic drug use can result in unwanted extrapyramidal side effects
○ Refers to messing up the basal ganglia and essentially inducing a movement disorder
○ Because of DA blockade by D2 receptors
Describe the tuberoinfundibular pathway and the drugs used to modulate it
• Hypothalamic neurons release DA in pituitary to inhibit prolactin release
• Antipsychotic drug use (D2 receptor block) can cause side effects of hyperprolactinemia as well as interference with regulation of body temperature
○ Poikilothermia
• Also can affect appetite
○ Weight gain
LSD use led to the discovery of serotonin’s role in psychotic illness. What is that role?
• Activation of 5HT2A receptors was the basis for the hallucinatory effects of LSD
• Projections from brainstem nuclei to prefrontal cortical areas, limbic region, and striatum have important modulatory actions on DA and glutamate neurons
• 5HT2A subtype is located on glutamate pyramidal neurons in cortical regions and on dopamine nerve terminals in striatal and cortical pathways
• Mesocortical pathway
○ 5HT2A blockers increase the release of DA and thereby alleviate the negative symptoms
○ Normally, activation of serotonin receptors can cause negative symptoms
• Glutamate pyramidal system
○ Activation of 5HT2A receptors here in the PFC results in stimulation of DA neurons in the VTA
○ Increase DA release in mesolimbic pathway, and increase the positive symptoms
○ Thus, serotonin blockers alleviate positive symptoms
• End result, blocking 5ht2A receptors helps both postive and negative symptoms
Where did the glutamate hypothesis of psychotic illness come from?
• From observations that antagonists of NMDA receptor channel (ionotropic) exacerbated both psychosis and cognitive impairment in schizophrenic patients
○ Pencyclidine (PCP)
○ Ketamine
• Postulates - hypofunction of NMDA receptors located on GABAergic interneurons in the PFC leads to diminished inhibitor influences that affect both mesolimbic and mesocortical pathways
○ Giving rise to both positive and negative symptoms
What needs to happen for the cortex to increase mesolimbic DA release?
• Cortical glutamate neurons to VTA directly innervate and stimulate the mesolimbic DA neurons
• Activation of the cortical glutamate neurons leads to activation of mesolimbic DA neurons
• NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output
• Hypofunction in these cortical NMDA-glu neurons can result in loss of cortical GABA inhibition and increased activity of cortical glutamate neurons
○ Results in hyperactivity in the mesolimbic pathway and the positive symptoms of schizophrenia
What does glutamate do in the mesocortical system?
• Cortical - brainstem VTA activaiton will result in decreased mesocortical DA release
• Different population of cortical glutamate neurons regulate the mesocortical DA release
• Indirect via GABA interneurons in VTA that innervate the mesocortical DA neurons selectively
• Activation of the cortical glutamate neurons leads first ot activaiton of the VTA GABA interneurons, then inhibtion of the mesocortical DA neurons
• Again, NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output
• Hypofunction in these cortical NMDA-glu neurons can result in loss of cortical GABA inhibtion and increased activity of cortical glutamate neurons
○ Results in hypoactivity in the mesocortical pathway and negative symptoms of schizophrenia
What is the mnemonic for remembering all the antipsychotic drugs we talked about?
- T - tiny (thioridazine)
- H - hits (haloperidol)
- C - can (clozapine)
- M - medicate (molindone)
- O - our (olanzapine)
- Q - quacks (quetiapine)
- R - reliant (on) (risperidone)
- Z - zeroing (in) (ziprasidone)
- A - anatomically (aripiprazole)
What’s important to keep in mind concerning the balance of D2 receptor block vs. other NT system blocks?
- All effective agents block D2 recpeotors
- However, degree of D2 receptor block related to other NT system block varies
- NE, Ach and glu interact a ton with the DA pathway
- Muscarinic, alpha1, and histamine blockade can explain adverse effects
What are the two main categories of antipsychotics?
- Typical and atypical
- (1st gen vs. 2nd gen)
- Relies on ratio of DA to 5HT2A receptor blockade
What makes an antipsychotic “typical”?
• 1st gen
• High D2/5HT2A ratio corresponding to good D2 block and good efficacy in modulating positive symptoms
• Also high incidence of extrapyramidal toxicity
○ High clinical potency - holoperidol (lower dose, but greater SE risk)
○ Low clinical potency - chlorpromazine (higher dose but less SE toxicity)
§ These have other SE like antimuscarinic, alpha1 blockade and antihistamine action
§ Dry mouth, sedation, hypotension
What makes an antipsychotic “atypical”?
• 2nd gen • Low D2/5HT2A ratio • Good efficacy against negative symptoms and some efficacy against postitive symptoms • Also thought to be better in treatment-resistent individuals ○ Aripiprazole ○ Olanzapine ○ Quetiapine ○ Clozapine • Less extrapyrmidal problems
Which antipsychotics have high hypotensive side effects?
- Penothiazines (aliphatic) - chlorpromazine
- Medium - thioxanthene - thiothixene
- Medium - dibenzodiazepine - clozapine
Which antipsycotics have a very low D2/5HT2A ratio?
• Clozapine and risperidone
Which antipsychotics have a high D2/5HT2A ratio?
- Thiothixene (very high)
- Haloperidol (very high)
- Chlorpromazine (high)
- Fluphenazine (high)
Which antipsychotics have a high sedative action?
- Phenothiazines (aliphatic) - chlorpromazine
- Medium - thienobenzodiazepine - olazapine
- Medium - dibenzothiazepine - quetiapine
- Medium - thioxanthene - thiothixene
What are the two drugs in the list that have a LOW clinical potency?
- Dibenzothiazpines - quetiapine
* Aliphatic phenothiazines - chlorpromazine
What are the extrapyramidal symptoms to worry about?
- Because of DA block, high in haloperidol
- Acute dystonia (onset 1-5 d): Torticollis, swollen tongue, trismus, oculogyric crisis, opisthotonos. Treatment: Antimuscarinic agents (diphenhydramine, benztropine).
- Akathisia (onset 6-60 d): Motor restlessness, inability to sit still (not anxiety or agitation). Treatment (difficult): Reduce dose or change drug; add anticholinergic and / or possibly β-blocker, benzodiazepines.
- Pseudoparkinsonism (onset 5-90 d): Tremor, bradykinesia, rigidity, shuffling gait. Treatment: Anticholinergic agents or amantadine (dopamine agonist).
- Tardive dyskinesias (onset 3-6 months, [?] supersensitivity of dopamine receptors): Involuntary repetitive movement of lips, tongue, choreoathetoid movements of arms, legs. Worsens upon withdrawal of antipsychotic drug. Common in elderly women; usually irreversible; overall 20-40% incidence with chronic treatment. Treatment: Rarely effective, so must weigh benefit-risk ratio for use; best strategy is prevention.
What are the “other effects” to be cognizant of?
• Agranulocytosis with clozapine • Hypersalivation • Weight gain ○ Diabetes, more with atypicals • Photosenstitivity • Lowered seizure threshold • Retinopathy (thiordazine) • Neuroleptic malignant syndrome ○ Rare ○ Catatonia, stupor, fever, unstable BP ○ Treat with sodium dantrolene (dantrium)
If you need to treat with dantrium, what is likely going on?
• Bad, rare side effect of antipsychotic use
• Neuroleptic malignant syndrome
○ Rare
○ Catatonia, stupor, fever, unstable BP
○ Treat with sodium dantrolene (dantrium)
What are the absorption properties of antipsychotics to keep in mind?
• They all have significant first pass effect
• Oral is extended release and chronic
○ Olanzapine, risperidone, clozapine
• IM is rapid treatment or for oral contraindications
○ Chlorpromazine, haloperidol, olanzapine aripiprazole
• IM dpot suspensions can be used to improve adhereance
What is up with distribution in antipsychotics?
• Most are extensively protein bound in plasma
○ 85%
• High lipid solubility and long 1/2 lives
• CROSSES PLACENTA
What is the excretion route of antipsychotics?
- Little work done by kidney
- Assume full metabolisim to more polar substances by P450 system phase 1
- Then conjugated
- Can be excreted in breast milk
As far as control of positive symptoms goes is atypical or typical better?
- For postive symptoms, equal
* The question is EPSE systems or not
When should clozapine be used?
- In patients refractory to other drugs
- Agranulocytosis and weight gain is a problem
- Olanzapine is alternative, watch for weight gain and diabetes
How can you characterize psychosis?
*BIG PICTURE - symptom of brain dysfunction. not necessarily psychoisis = schizophrenia
• Typically characterized by derangement of personality and loss of contact with external reality
• Other signs include depression, anxiety, cognitive dysfunction including disturbances in attention, learning, and memory and delirium
• Appears as a symptom of a number of mental disorders, including mood and personality disorders, schizophrenia, delusional disorder and substance abuse
Describe the primary disorder in thinking present in psychotic patients.
- They hear voices and have other sensations that are not real (hallucinations)
- They believe that they are influenced by unseen forces around them (paranoid delusions) or are being tormented, harmed, followed, tricked or spied on (persecutory delusions)
- Have other disorders in thought, typically idiosyncratic associations that are evidenced in disorganized speech or writing. (formal thought disorder)
The positive symptoms of schizophrenia are believed to result from what NT systems being dysfunctional?
• Positive symptoms = delusions and hallucinations
• Overactivity of DA neurons in mesolimbic system
○ Too much emotional valence
• Underactivity of gluatamte neurons in frefrontal cortex
○ Too little inhibition and modulation of sensory modalities
