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Schizophrenia. Individuals with schizophrenia have many different symptoms Including hearing voices Unrealistic beliefs Disorganized communication Often need to be hospitalized Schizophrenia is a chronic condition Drugs or environmental toxins can cause acute psychosis
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Schizophrenia • Individuals with schizophrenia have many different symptoms • Including • hearing voices • Unrealistic beliefs • Disorganized communication • Often need to be hospitalized • Schizophrenia is a chronic condition • Drugs or environmental toxins can cause acute psychosis • Despite therapy about 30% of people with schizophrenia spend a significant portion of their lives in mental hospitals • About 1-1.5% of the population will suffer from schizophrenia • 2-3% will suffer from less severe symptoms that do not meet the diagnostic criteria
Symptoms of schizophrenia • Symptoms usually begin during late teenage years and early twenties • can occur in childhood • Affects men and women equally • Clear gender difference in onset • Men more likely to get the disease early in life • Women more likely to get the disease later in life
No defining cluster of symptoms • Schizophrenia is a thought disorder • Illogical thinking • Lack of reasoning • Inability to recognize reality • Specific symptoms are quite variable for each individual • Disturbance of perception (hallucinations) are common • Usually auditory
Symptoms of schizophrenia • Sometimes the voices can be familiar like a parent or spouse • Sometimes unrecognized • Foreign agents • Radio transmitter in head • Voices of angels • Often the voices are critical, demanding, or accusatory • Sometimes can direct the person to perform destructive behaviors
Symptoms of schizophrenia • Recently researchers have imaged the brain during hallucinations • Some consistent findings are • Usually left cerebral hemisphere is more activated • Typical language hemisphere • Most active areas are in the audio linguistic association cortex • Rather than primary cortex • Consistent with the internally generated nature of the experience • Some have hypothesized that auditory hallucinations are like “inner speech” • But Broca’s area is often not activated • Wernicke’s area is usually activated • Electrical stimulation of this area can cause hallucinations in a healthy individual
Symptoms of schizophrenia • During visual hallucinations • Activation of visual association cortex • Interestingly there is also often deep brain activity • Including thalamus and limbic system • Probably contributes to the emotionality of the experience
Symptoms of schizophrenia • Bizarre delusions (false beliefs) are also common • Delusions of persecution • People are spying on them • Planning to do them harm • Delusions that one’s thoughts are being broadcasted to others • Delusion that thoughts are from an outside source • Often outer space
Symptoms of schizophrenia • Emotional disturbances are also common • Emotions might be absent • Flattened affect • Monotone voice • Emotions may be inappropriate to the situation • Laughing or smiling when discussing a tragic event • Can sometimes have unpredictable changes in mood
Symptoms of schizophrenia • People with schizophrenia are frequently withdrawn • Preoccupied with their own thoughts or delusions • Often don’t perform everyday activities like maintain personal hygiene • Often have motor disturbances • Inappropriate or bizarre postures • Stereotyped movements • Twirling hair • Rocking or pacing • Some forms of schizophrenia (particularly paranoid) can lead to agitation and violence
Diagnosis • Diagnosis is not simple • No two individuals show identical patterns • Nor is there a single symptom that all people with schizophrenia share • Symptoms can increase and decrease over time • Some believe that schizophrenia represents a cluster of disorders rather than a single disorder
Historically schizophrenia was categorized into subtypes • Catatonic • Alternating periods of immobility and excited agitation • Can be completely unable to move • May flail about – pace in a frenzy • Extreme resistance – won’t respond to any attempt to be moved or speak • Mimicking speech (echolalia) or movement (echopraxia) • Paranoid • Delusions of grandeur or persecution • Auditory hallucinations
Hebephrenic also known as disorganized • emotional responses can often seem strange or inappropriate to the situation. • Inappropriate facial responses may be common • behavior is sometimes described as 'silly', such as inappropriate laughter • Complete lack of expressed emotion is sometimes seen • indifference, anhedonia (the lack of pleasure), • avolitiion (a lack of motivation). • Undifferentiated • Doesn’t fit the criteria of the other subtypes
Another classification scheme refers to positive and negative symptoms of schizophrenia • Positive symptoms (too much) • Delusions • Hallucinations • Disorganized speech • Bizarre behavior • Patients with primarily positive symptoms tend to be older when they get the disease • Appear relatively normal in younger years • Respond well to conventional antipsychotic medications • Block Dopamine receptors • Symptoms escalate with drugs that enhance dopamine
Negative symptoms (too little) • Reduced speech (alogia) • Flattened affect • Loss of initiative and motivation (avolition) • Social withdrawal • Loss of ability to derive pleasure in life (anhedonia) • Intellectual impairment • Tend to show early onset of some symptoms • Long course of progressive deterioration • Resistant to classical antipsychotics • Newer atypical antipsychotics can help • Evidence that neurodegeneration may play a role
Pharmacological treatment has revolutionized treatment of schizophrenia • Prior to advent of drug treatment there were few options for patients with schizophrenia • Restrained in hospitals • Shock and insulin induced seizures • Prefrontal lobotomy • Since the advent of 1950s • Hospitalization began to decline • Concided with the drug chlorpromazine (thorazine)
Preclinical Models of Schizophrenia • Schizophrenia is primarily a thought disorder • Difficult to develop animal models • Stimulant models of schizophrenia • High doses of stimulants have been used to model schizophrenia • Amphetamine and cocaine can cause psychosis in humans • Paranoid delusions • Stereotyped, compulsive behaviors • Visual and auditory hallucinations • Trained clinicians can have difficulty distinguishing • If patients with schizophrenia take amphetamines their symptoms get worse • Amphetamine induced psychosis responds to the same drugs used to treat schizophrenia
In animals high doses of amphetamines • Cause stereotyped sniffing, licking, gnawing • Known as amphetamine-induced stereotypy • Similar to repetitive motions in schizophrenia • Amphetamine-induced stereotypy is a classic screening device for antipsychotics
Another animal model that is used is blockade of apomorphine-induced motor activity • Apomorphine is a dopamine agonist that causes increased activity in rats. • It has been shown that drugs that reduce apomorphine induced running are consistently effective antipsychotics • Researchers usually compare the dose that will block apomorphine activity (related to therapeutic effect) • With dose that will produce catalepsy (related to locomotor side effects) • The farther apart those two dose response curves are the more likely the drug will be effective without producing motor side effects
PCP-induced psychosis • PCP-induced psychosis • Original observation in humans serves as the basis for the dopamine-glutamate hypothesis of schizophrenia • The symptoms of high doses of PCP include • Disorientation, Muteness, Cognitive impairments • Can sometimes cause paranoid delusions • Motor symptoms • Agitation, Grimacing, Rigidity, Catalepsy, Tremors • Again – closely resembles schizophrenia • Repeated use of PCP can cause long-lasting psychotic symptoms • PCP has also been used as animal model of schizophrenia • What is interesting about this model is that it can cause both positive and negative symptoms • Remember that PCP antagonizes glutamate in addition to causing increases in DA activity
Prepulse inhibition of startle model • Prepulse inhibition of startle (PPI) • People with schizophrenia seem to have difficulty screening out irrelevant information • One theory is that because they fail to screen out this information they become bombarded by stimuli • Leading to sensory overload • Fragmented thinking • Thought disorder
PPI • Here’s how it works • Normally a loud noise causes a strong startle response • However, if a quieter noise occurs just prior to the loud noise the startle response is reduced • Prepulse can occur 30-500 ms before • It is too weak to produce startle itself
PPI • The startle response is a simple reflex, however the inhibition of this reflex involves a complex neuroanatomical circuit • Including • Limbic cortex, striatum, globus pallidus, Pontine reticular formation • All of these brain areas show abnormalities in patients with schizophrenia • Thus, it is not surprising that patients with schizophrenia show diminished PPI
PPI • PPI has several advantages that make it an appealing animal model • It is a simple measurement (startle reflex) which produces reliable results • All mammals including primates exhibit PPI and do not require training to show it • In humans they often measure eyeblink • In rats they often measure whole-body flinch
PPI • PPI is disrupted by systematic administration of dopamine agonists. • Like apomorphine • PPI is reinstated by dopamine receptor-blocking antipsychotic drugs • Including the atypical antipsychotics (like clozapine) • Because these drugs reinstate PPI at clinically relevant doses it further validates this method as a treatment screening device • Positive correlation • Drugs that treat schizophrenia at low doses reinstate PPI at low doses • High = high • See next slide
Box 18.2 Animal Model—Prepulse Inhibition of Startle (Part 3)
PPI is also disrupted by • systematic exposure to serotonergic agonists • Glutamate antagonists • Surgical manipulation of the cortical-striatal-pallidal-pontine circuit • This parallels structural and functional abnormalities that have been identified in schizophrenic patients • Thus, this model may allow researchers to study unique aspects of the pathology of schizophrenia
PPI • Another reason the PPI model is very appealing is because it responds to genetic and environmental manipulations • Genetically distinct strains of rats differ in how responsive they are to dopaminergic modulation of PPI • Rats bred for apomorphine sensitivity or lack of sensitivity show more and less inhibition of PPI respectively • This may be useful as a model for how genes might code for DA-induced gating disruption • Which may provide insight into susceptibility to schizophrenia • Developmental influences can have effects as well • Isolation stress early in life can reduce PPI • This effect is reversed by antipsychotic drugs.
Classic Neuroleptics and atypical antipsychotics • Drugs used to treat schizophrenia are called antipsychotic drugs or neuroleptics • Commonly divided into two classes • Traditional neuroleptics • Second generation (atypical) antipsychotics • No drug is consistently better than any other, but an individual may be responsive to a particular drug
Traditional Neuroleptics • Chlorpromazine (thorazine) was the first neuroleptic to be used in psychiatry • By making slight changes to the chemical structure many neuroleptics have been created • See Figure 18.4 for a listing
Pharmakokinetics of traditional neuroleptics • The traditionally neuroleptics are traditionally given orally • Sometimes given IM for patients that are unable or unwilling to take the drug • The drugs are distributed throughout the body with the highest concentrations in the liver and lungs • Binding to inactive sites like blood proteins and fats is common • Release from these sites is slow • Leading to a very slow rate of elimination • Metabolism is also quite slow • Metabolites can be found in the urine many months after termination of treatment • Thus, the half life is quite long (11-58 hours) • Only a single dose is needed per day
Effectiveness of traditional neuroleptics • As we mentioned earlier the introduction of neuroleptics dramatically improved the treatment of schizophrenic patients • Works for a significant number of the patient population • Reduce symptoms • Decrease average hospital stay • Calm agitated patients • Open up patients that are more withdrawn • just a few doses can eliminate hyperexcitability or manic behaviors • Positive symptoms such as delusions, hallucinations, and disordered thinking gradually improve over several weeks • Negative symptoms are more resistant
Effectiveness of traditional neuroleptics • Law of thirds • One third of patients treated respond well • One third of patients show significant improvement but may relapse from time to time • One third of patients don’t respond well • Some fail to respond at all • This category may represent a large portion of the homeless population in the US • Following initial recovery antipsychotics are prescribed to prevent relapse • The drugs do have side effects • so often patients fail to continue treatment
When the antipsychotics were introduced in the 1950s scientists had no idea how they worked • chlorpromazine was administered as a treatment for severe vomiting and as a sedative for presurgical patients • One thing that was noticed was that there was a connection between improved symptoms and Parkinson’s like motor problems • By the early 1960s the biochemical nature of Parkinson’s disease was beginning to be understood. • deficiency in the DA releasing neurons of the midbrain. • This led to the development of Parkinson’s drugs • Also provided insight to the mechanism of neuroleptics • positive effects seemed to be due to decreasing DA function • L-Dopa treatment could lead to psychotic symptoms in Parkinson’s patients
It is now know that the effectiveness of neuroleptics is correlated with their ability to antagonize DA • binding effectiveness (x-axis) • dose at which 50% of receptors are bound • therapeutic dose (y-axis).
Neuroleptics also bind to serotonin receptors, but there is no clear relationship between binding effectiveness (x-axis) and therapeutic dose (y-axis).
You probably recall that there are many subtypes of DA receptors • The typical neuroleptics block the D2 receptor to varying degrees. • D2 receptors occur both postsynaptically and presynaptically as autoreceptors. • so again (like with depression) we have a complex interaction of systems • it takes several weeks for neuroleptics to reach full effectiveness. • thus, like with depression, it is likely that it is synaptic changes related to DA turnover and effectiveness that contribute to the positive effects
The traditional neuroleptics have significant side effects • The effect of the traditional neuroleptics on the D2 receptors likely leads to the significant side effects that these drugs have. • Parkinsonism • classic antipsychotics cause a movement disorder • tremors • akinesia (slowing or loss of movement) • muscle rigidity • akathesia (feeling of discomfort in the legs) • hard to sit still • One way to treat Parkinson’s disease is to reduce acetylcholine activity • Thioridazine is an antipsychotic that also has anticholinergic action • making it less likely to cause Parkinsons • sometimes antipsychotics are prescribed along with an anticholinergic drug
Tardive dyskinesia • stereotyped involuntary movements • particularly of the face and jaw • lip smacking, lateral jaw movements, tongue movements • also uncontrolled movements of arms and legs. • clip • Incidence of Tardive Dyskinesia goes up dramatically with chronic treatment
Neuroendocrine effects • breast enlargement and tenderness • decreased sex drive • lack of menstruation • increased prolactin levels (can lead to lactation) • inhibition of growth hormone release • problem for medicating adolescents • weight gain • neuroleptic malignant syndrome • fever • rigidity • altered consciousness • autonomic nervous system instability • rapid heart rate • blood pressure fluctuations • can be fatal
additional side effects • can have anticholinergic effects • dry mouth • blurred vision • constipation • difficulty in urination • can have antiadrenergic effects • dizziness • fainting
atypical antipsychotics • atypical antipsychotics • fewer motor system side-effects • selective D2 receptor antagonists • sulpiride, raclopride, remoxipride • bind specifically to D2 and D3 receptors • thus, fewer ANS side-effects and less sedation
broad-spectrum antipsychotics • block a broader spectrum of receptors. • clozapine • weak affinity for D1 and D2 • high affinity for D4 • substantial affinity for serotonin, muscarinic, and histamine receptors • blocks apomorphine hyperactivity, but no catalepsy • not more effective for postive symptoms than typical neuroleptics • can be effective in patients that don’t respond to traditional medications • also can reduce negative symptoms • can take 5 months of treatment to be fully effective • not known why • The idea here is that increased activity at say D4 or serotonin sites can compensate for some of the D2 effects.
clozapine • has side effects • increased likelihood of seizures • weight gain • cardiovascular problems • one side effect is particularly dangerous • can cause agranulocytosis • decrease in granulocytes • a type of white blood cell • infections of skin and throat and lungs can occur • Risperidone (risperdal) • broad spectrum antipsychotic that doesn’t have the risk for agranulocytosis
Dopamine stabilizers • aripiprazole (Abilitat) • Dopamine partial agonist • binds to DA receptors • produces less effect than DA itself • in the presence of a lot of DA • antagonist • in the presence of little DA • agonist • by reducing too much DA activity positive symptoms may be reduced • by increasing DA activity in areas where little activity is occuring negative symptoms may be reduced • Has fewer side effects than many of the drugs
Neurochemical models of schizophrenia • DA imbalance hypothesis • too little DA function in mesocortical neurons • negative symptoms • impaired thinking • due to impaired prefrontal cortex activity • too much DA activity in mesolimbic neurons • positive symptoms
18.17 Schematic representation of the neurodevelopmental model of schizophrenia • Neurodevelopmental model of schizophrenia (Weinberger, 1987) • Negative symptoms are associated with reduced frontal lobe function • resemble the symptoms of patients that have had frontal lobe lesions • frontal lobotomy • Positive symptoms are the result of decreased inhibitory feedback from the frontal cortex to limbic sites.