Schizophrenia and Psychotic Disorders

• Psychotic disorders involve a disconnection from reality, causing misinterpretations of events and inappropriate responses.
• Individuals experiencing psychosis can exhibit hallucinations and delusions, which are beliefs with no basis in reality.
• Psychosis can be brief, triggered by substances, or a chronic condition, emerging anytime from early adulthood onward.

Schizophrenia

• Schizophrenia encompasses a range of psychoses, characterized by a separation between thought, emotion, and behavior, not split personalities.

DSM-IV-TR Diagnostic Criteria

• Requires two or more of the following symptoms present for a significant portion of a 1-month period:
  • Delusions
  • Hallucinations
  • Disorganized speech
  • Grossly disorganized or catatonic behavior
  • Negative symptoms like affective flattening, alogia, or avolition
• Only one Criterion A symptom is required if delusions are bizarre or hallucinations involve voices commenting on the person's behavior or multiple voices conversing.

Symptom Classification

• Positive symptoms are traits abnormally present in psychosis, such as hallucinations and delusions.
• Negative symptoms are traits abnormally absent in psychosis, including affective flattening, anhedonia, alogia, and avolition.
• Cognitive deficits involve attention, learning, memory, problem-solving, abstract thinking, and slowed neuromuscular actions.

Symptom Appearance

• Schizophrenia symptoms typically emerge gradually over 3-5 years, starting with negative symptoms before positive ones.
• Men and women are equally affected, with men showing symptoms earlier (late teens or early twenties) than women (twenties or thirties).

Incidence and Risk Factors

• Schizophrenia has a worldwide incidence of about 1%, consistent across different demographics.
• Having a close relative with schizophrenia can increase the risk up to 10 times, with identical twins facing a nearly 50-fold increase.
• Genetic factors play a crucial role, with multiple gene mutations creating vulnerability.

Environmental Influences

• Environmental factors are crucial for activating genes linked to schizophrenia.
• Maternal viral infections during pregnancy may affect fetal brain development that results in schizophrenia.
• Incidence is higher in large cities and during winter, which may be linked to lower vitamin D levels.
• Other risk factors include birth complications, early childhood infections, head trauma, stress, and drug use.

Theories of Schizophrenia

• Schizophrenia results from a genetic predisposition combined with environmental triggers.
• Positive symptoms are linked to hyperactivity at mesolimbic dopaminergic synapses.
• Negative and cognitive symptoms arise from degeneration in the brain causing hypoactivity at mesocortical dopaminergic synapses.
• Dysfunctional glutamate neurotransmission, along with involvement of serotonin, GABA, acetylcholine, and histamine is also implicated.

Brain Abnormalities

• Brains of schizophrenic individuals show structural abnormalities that lead to functional disturbances.
• Enlarged lateral and third ventricles suggest loss of brain tissue.
• Less brain tissue volume is apparent in numerous brain regions
• Deterioration is significant in areas of the frontal and temporal lobes, corpus callosum, and cerebellum, including the limbic system.
• Volume deficits are progressive, worsening with symptoms.
• Deterioration of the cingulate gyrus correlates with decreased social functioning.
• Volume loss in the dorsolateral prefrontal cortex impairs cognitive functioning and working memory.

Neurophysiological Processes

• Abnormal processes may start before birth and continue through adolescence.
• Children at high risk for schizophrenia show speech, neuromotor deficits, and cognitive warning signs.
• Synaptic pruning during childhood is pathologically exaggerated, leading to a loss of connections and neuron numbers.

Dopamine Hypothesis

• The Nigrostriatal Pathway dopamine neurons originate in the substantia nigra and project to the dorsal striatum, essential for smooth movement integration.
• Dopamine deficiency leads to extrapyramidal signs and symptoms (EPS) similar to Parkinson's.
• Antipsychotic drugs block dopamine activity in this pathway, causing serious EPS.
• The Mesocortical Pathway and Mesolimbic Pathway dopamine systems originate in the ventral tegmental area.
• The mesocortical pathway projects to the cortex; the mesolimbic pathway projects to the nucleus accumbens and limbic structures.

Basic Tenets

• Schizophrenia results from excessive dopamine activity which is supported by:
  • Drugs increasing dopamine can produce schizophrenia-like positive symptoms.
  • Available antipsychotics were dopamine antagonists.
• Research has linked the effectiveness of antipsychotics to their dopamine-blocking ability.
• Effective antipsychotics cause EPS, similar to dopamine depletion in Parkinson's disease.
• The most effective drugs have the greatest ability to block dopamine receptors.

Revised Dopamine Hypothesis

• Haloperidol's effectiveness despite lower dopamine receptor affinity led to the discovery of dopamine receptor subtypes (D1 and D2).
• Therapeutic effect correlates with affinity for D2 receptors, not D1.
• Many antipsychotics bind more tightly to D2 receptors than dopamine.
• Revised hypothesis: Schizophrenia results from excessive dopamine activity specifically at D2 receptors.

Inconsistencies and Further Revisions

• Inconsistencies remain in research comparing D2 receptor densities in schizophrenic and non-schizophrenic individuals.
• Antipsychotics do not work immediately despite blocking dopamine, suggesting a more complex mechanism.
• Negative and cognitive symptoms do not improve with D2 receptor blockade.
• Current revision suggests excessive dopamine in the mesolimbic pathway causes positive symptoms.
• Negative and cognitive symptoms result from a lack of dopamine in the mesocortical pathway.
• Frontal lobe hypoactivity may drive hyperactivity in the mesolimbic dopamine system.

Glutamate Hypothesis

• Dissociative drugs like phencyclidine (PCP) and ketamine produce symptoms similar to those of schizophrenia, therefore providing support.
• These drugs bind to the PCP binding site within the glutamate NMDA receptor.
• The ability of compounds to cause schizophrenia-like symptoms is related to their ability to antagonize glutamate function.

Neural Information

• Glutamate neurons are ubiquitous as glutamate is the primary excitatory neurotransmitter.
• Most information leaving, traveling between, and entering the cortex does so through glutamate neurons.
• Genetic factors predispose individuals to glutamate hypoactivity, specifically at the NMDA receptor.
• Genes contributing to schizophrenia influence glutamate neuron connectivity, synaptogenesis, and neurotransmission at the NMDA receptor.
• Dysfunction may arise from neurodevelopmental abnormalities or synaptic overpruning.

NMDA Receptor Antagonists

• CSF levels of glutamate are similar between schizophrenic and non-schizophrenic individuals.
• NMDA receptor antagonists actually increase glutamate release in the prefrontal cortex.
• Blockade of AMPA receptors reverses the effects of NMDA receptor antagonists.
• Glutamate dysfunction involves NMDA receptor hypoactivity and AMPA receptor hyperactivity.

GABA Interneurons

• Neurons in the cortex are inhibited by GABA interneurons.
• Blocking NMDA receptors on GABA interneurons reduces their firing, resulting in inhibition of inhibition.
• This leads to increased glutamate release and activation of AMPA receptors.
• One goal of antipsychotic drug development is to stabilize NMDA and AMPA receptor glutamate neurotransmission in the cortex.
• Indirect NMDA agonists, such as glycine and d-serine, facilitate NMDA receptor activity.

Synthesis

• Schizophrenia develops gradually, with negative and cognitive symptoms followed by positive symptoms.
• Brain region deterioration begins in utero and continues through childhood, accelerating during synaptic pruning.
• Loss of glutamate synapses leads to NMDA receptor hypoactivity and glutamate dysregulation.
• NMDA receptor activity regulates dopamine function.
• Glutamate neurons in the prefrontal cortex project to the ventral tegmental area, synapsing with dopaminergic neurons.

Cortical Glutamate

• Cortical glutamate neurons excite mesocortical dopamine neurons, which project back to the prefrontal cortex, releasing dopamine.
• Prefrontal cortical glutamate neurons synapse with GABAergic interneurons within the ventral tegmental area.
• GABAergic interneurons inhibit dopaminergic neurons that project to the nucleus accumbens.
• Glutamate activity in the prefrontal cortex inhibits dopamine neurons that form the mesolimbic pathway.

Neurotransmitter Systems

• Decreased cortical glutamate activity results in understimulated ventral tegmental area dopamine neurons.
• This leads to hypoactivity in the mesocortical dopamine pathway and hyperactivity in the mesolimbic dopamine pathway.
• Implies why the emergence of negative, cognitive, and then positive symptoms of schizophrenia progression is seen.
• Neurotransmitter systems implicated include serotonin, GABA, acetylcholine, and histamine.

Discovery of Antipsychotic Medications

• Henri Laborit sought a preoperative medicine to relieve anxiety and reduce surgical shock.
• Laborit experimented with drugs blocking epinephrine, acetylcholine, and histamine.
• Chlorpromazine, initially rejected as an antihistamine, was found to have impressive tranquilizing effects.
• Delay and Deniker administered chlorpromazine in higher doses and reported successes in agitated mental patients.
• In 1953, Largactil was marketed in Europe.

Chlorpromazine

• Marketed as Thorazine in the United States in 1955.
• Introduction of chlorpromazine led to a dramatic decline in the number of patients in mental hospitals.
• Resident population of mental institutions dropped by 80% due to the use of antipsychotics.

Terminology

• Antipsychotics diminish symptoms of psychosis.
• Major tranquilizers inappropriately suggests that drugs are only useful for tranquilizing agitated patients.
• Neuroleptic refers to the capacity of drugs to cause extrapyramidal symptoms (EPS), such as rigidity and difficulty of movement.
• EPS is a bothersome side effect.
• The term antipsychotic is used because it focuses on the useful effects rather than side effects.

Medication Types

• Typical (first-generation) antipsychotics were developed before 1975 and include phenothiazines and butyrophenones.
• These primarily block D2 receptors and are most effective in treating the positive symptoms of psychosis.
• Adverse EPS are typical of these drugs.
• Atypical (second-generation) antipsychotics are pharmacologically different from typicals.
• They have a weak affinity for the D2 receptor, binding loosely.
• Adverse EPS are atypical effects of these drugs.
• Atypicals tend to have high affinities for D3 and D4 receptors.

EPS Production

• Positron emission tomography research reveals that 60-80% of D2 receptors must be occupied in the striatum to produce EPS.
• Atypical antipsychotics avoid blocking dopamine in the nigrostriatal system, causing fewer EPS.
• They have high affinities for D3 and D4 receptors which are not found in the basal ganglia.
• Atypical antipsychotics can depress dopamine activity in the mesolimbic system and treat psychoses without affecting the nigrostriatal system.

Neurotransmitter Blocking

• Both typical and atypical antipsychotics have some 5-HT2A blocking ability.
• Atypicals tend to have greater effects at 5-HT2A receptors than at D2 receptors.
• 5-HT2A receptor activation by drugs like LSD and psilocybin produces psychotic symptoms.
• Interaction between metabotropic glutamate (mGlu) receptors and 5-HT2A receptors creates vulnerability to psychosis.
• 5-HT2A–mGlu receptor complex may be ideal for antipsychotics to target.

Other Transmitters

• Atypical antipsychotics affect acetylcholine, histamine, norepinephrine, and peptide transmitters such as GABA.
• These may contribute to therapeutic efficacy and side effect profiles.
• Anticholinergic effects of some atypicals provide an additional mechanism for reducing EPS.
• Some of these additional actions may cause unpleasant or dangerous effects.
• The first atypical was clozapine, which alleviates positive, negative, and cognitive symptoms of schizophrenia.
• Clozapine has a high affinity for D4 receptors, multiple 5-HT receptor subtypes, muscarinic acetylcholine receptors, and alpha1 adrenergic receptors.
• Its primary therapeutic effects are thought to result from antagonism of D4 and 5-HT2A receptors
• Aripiprazole (Abilify) is sometimes referred to as a third-generation antipsychotic.
• Aripiprazole is a DA receptor partial agonist - it modulates dopamine activity at D2, D3, and D4 receptor subtypes.
• Aripiprazole acts as an agonist in regions of low dopamine activity and as an antagonist in regions of high dopamine activity.
• Stabilizes dopamine activity, treating positive, negative, and cognitive symptoms of schizophrenia.

Symptoms

• Atypicals are not overwhelmingly superior to typicals in relieving symptoms of schizophrenia.
• In some cases and for certain symptoms, they may be less efficacious.
• The greatest benefit is their lack of EPS.

Routes of Administration

• Antipsychotics are usually taken orally but are available in intramuscular or intravenous injection forms.
• Injected when used as a presurgical or preanesthetic medication.
• Intravenous injection avoids irregularities in absorption from the digestive system.
• Intramuscular administrations are utilized to patients that are agitated.
• Depot injection is used for chronic patients to release medication over time.

Depot Injections

• Typical antipsychotics can be dissolved in an oily base and injected intramuscularly.
• Newer atypical antipsychotics administered as depot injections are not suspended in oil.
• Risperidone can be encapsulated in a biodegradable polymeric microsphere preparation.
• Olanzapine and paliperidone can be combined with the salt form of pamoic acid.
• A single depot injection may be effective for as long as 4 weeks.

Absorption And Distribution

• Most antipsychotics are absorbed from the digestive system.
• Once absorbed, easily cross placental and blood–brain barriers.
• Blood protein binding is considerable, and the drugs tend to be absorbed into body fat and released slowly.
• Depot injections accumulate in body fat over time
• Long-acting risperidone reaches peak release at about 28 days.
• Olanzapine and paliperidone show peak blood levels after about 2 to 4 days.

Excretion

• Undergo extensive metabolism after excretion.
• There is considerable individual variability in the metabolism of antipsychotics.
• Trial and error is necessary to find the best dose.
• Protein binding and tendency to stay in body fat means antipsychotics stay in body fat.
• The cytochrome P450 enzymes play a major role in the metabolism of antipsychotics.
• Individuals taking antipsychotics are at increased risk of renal failure.

Body Effects

• The effects of antipsychotics depend on the individual and drug.
• The effectiveness as an antipsychotic varies.
• Treatment is life long but can cause harm to body.
• The most pronounced side effect of the typical antipsychotics is EPS(alterations in movement that resemble the symptoms of Parkinson’s disease).
• 40% of typical antipsychotics patients develop EPS.
• 20% of patients show akathisia, a condition characterized by uncontrolled restlessness and compulsiveness.
• Prolonged use of typicals can lead to tardive dyskinesia due to fat soluable composition.
• Atypicals have are less fat soluble and bind only briefly to D2 receptors results in a very low chance of tardive dyskinesia.

Clozapine

• Clozapine can result in increased risk of agranulocytosis.
• Patients must be monitored with blood testing when taking clozapine.
• The Typicals can increase susceptability to heat stroke or hypothermia, due to problems regulating temperature
• Additional, side effects include weight gain, cardiac function changes, dry mouth, and more.
• Atypicals have less chance of creating EPS.
• Atypicals side effects include glucose metabolism, weight gain, onset of diabetes, thermoregulation, dry mouth,dizziness and more.
• People taking atypical antipsychotics also experience thermodysregulation, dry mouth, dizziness, nausea, and are more prone to developing cataracts.
• Aripiprazole has a relative absence of side effects compared to typicals.

Sleep Effects

• Antipsychotics at therapeutic doses have little effect on sleep.
• Sedating effects will increase sleep time with high doses
• The antipsychotics do not alter sleep cycles or REM sleep.
• There is evidence that the atypicals may increase the risk of obstructive sleep apnea.

Lethal Effects

• Not lethal, instead are extremely safe and have a high therapeutic index.
• 1 to 100 is a typical antipsychotics therapeutic index.
• It is practically impossible to use antipsychotics to commit suicide.

Behavior Effects

• Chlorpromazine, when given to healthy subjects, causes a very pronounced feeling of tiredness.
• Haloperidol is not as sedating as chlorpromazine, but it makes subjects feel internally aroused and externally sedated at the same time.
• Many of the atypical antipsychotics dont generate un pleasant feelings.

Performance Effects

• Attention and cognitive performance may be variable with typical antipsychotics.
• Acute effects may be related to sedative effects, and tolerance can occur within 14 days.
• Clozapine and remoxipride have been shown to interfere with performance.

Animal Behavior

• Remarkable effect is that they suppress spontaneous movement in an open field and can render animals immobile.
• Given rise to the name of neuroleptic
• Diminish the frequency and intensity of attack behaviors.

Conditioned Behaviour

• Cause a decrease in responding on schedules maintained by Reinforcment
• A lower dose may increase response rates
• Diminish avoidance behaviour at a dose that doesnt change escape behaviour
• First used to test on humans by Henri Laborit.

Discriminaition and Dissassociation

• Chlorpromazine will cause dissociation.
• In one study, rats trained on an avoidance task under the influence of chlorpromazine were unable to remember what they had learned.
• This has caused some concern among psychotherapists.

Drug Discrimination

• The antipsychotics are not well discriminated.
• Large doses and training trials are needed.
• Response will generalize to other antipsychotics.
• A rat trained to discriminate clozapine will not generalize to haloperidol or chlorpromazine.
• There is no generalization between the antipsychotics and the antidepressants.

Tolerance

• Effects dont decrease for years if kept at established dose.
• Haloperidol's ability to increase dopamine release in the cortex does decline with prolonged use.
• Clozapine does not show tolerance of this sort.
• Tolerance seems to develop to the sedating effects and EPS.

Withdrawal

• If it exist at all, physical dependence is rare or mild.
• Possible muscular discomfort, sleep difficult, and etc, from withdrawal.
• Slow excretion could be causing lack of of withdrawal symptoms.

Self Admin in humans

• Some drugs have aversive properties.
• Monkeys learned to bar press to avoid infusions after a week.
• The aversive properties of chlorpromazine develop slowly with frequent doses.
• Antipsychotics are never abused, but compliance and consistent treatment is difficult.
• Developed administration techniques that do not depend on the patient’s compliance
• Noncompliance is higher with typicals.