Schizophrenia

1. 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

2. 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

3. 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

4. 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

5. 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

6. Symptoms of schizophrenia

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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)

17. 18.2 Treatment of the mentally ill

18. 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

19. 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

20. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. Box 18.2 Animal Model—Prepulse Inhibition of Startle (Part 3)

30. 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

31. 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.

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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).

39. Neuroleptics also bind to serotonin receptors, but there is no clear relationship between binding effectiveness (x-axis) and therapeutic dose (y-axis).

40. 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

41. 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

42. 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

43. 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

44. additional side effects • can have anticholinergic effects • dry mouth • blurred vision • constipation • difficulty in urination • can have antiadrenergic effects • dizziness • fainting

45. 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

46. 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.

47. 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

48. 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

49. 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

50. 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.