Schizophrenia 24 (1) PDF

Schizophrenia Schizophrenia is a complex and multifaceted mental disorder with numerous theories and hypotheses attempting to explain its causes and underlying mechanisms. Comparison-role of different receptors in normal brain and in schizppherinia In the normal brain, various neurotransmitt...

Schizophrenia Schizophrenia is a complex and multifaceted mental disorder with numerous theories and hypotheses attempting to explain its causes and underlying mechanisms. Comparison-role of different receptors in normal brain and in schizppherinia In the normal brain, various neurotransmitter receptors play critical roles in regulating mood, cognition, perception, and behavior. In schizophrenia, the function and balance of these receptors are often disrupted, leading to symptoms such as hallucinations, delusions, and cognitive impairments. Dopamine Receptors Normal Brain:Dopamine plays a crucial role in regulating mood, motivation, reward, and movement. The dopaminergic system -dopamine receptors (D1, D2, D3, D4, and D5). D1 receptors are associated with excitatory neurotransmission, while D2 receptors play a role in inhibitory pathways. Both are important in cognitive and motor control. Dopamine Receptors  Schizophrenia:The dopamine hypothesis of schizophrenia suggests hyperactivity of D2 receptors, particularly in the mesolimbic pathway, leading to positive symptoms such as hallucinations and delusions.  In contrast, hypoactivity of dopamine in the prefrontal cortex, particularly D1 receptors, may contribute to negative symptoms (such as reduced emotional expression and social withdrawal) and cognitive deficits. Glutamate Receptors  Normal Brain:Glutamate is the primary excitatory neurotransmitter and plays a central role in synaptic plasticity, learning, and memory. The key glutamate receptors include NMDA (N-methyl-D-aspartate), AMPA, and kainate receptors.  NMDA receptors are critical for synaptic strength and neurodevelopment, especially in the prefrontal cortex and hippocampus. Glutamate Receptors Schizophrenia:The glutamate hypothesis posits that dysfunction in NMDA receptors, particularly hypofunction, contributes to the pathophysiology of schizophrenia. NMDA receptor hypofunction may lead to impaired cortical and hippocampal function, associated with cognitive deficits and Serotonin Receptors Normal Brain:Serotonin regulates mood, emotion, and cognition. There are several serotonin receptor subtypes, but the 5-HT1A, 5-HT2A, and 5-HT3 receptors are among the most relevant in brain function. Serotonin, through 5-HT2A receptors, influences dopamine release, particularly in the prefrontal cortex. Serotonin Receptors  Schizophrenia:Atypical antipsychotics, which target both dopamine and serotonin receptors (especially 5- HT2A), are effective in reducing positive symptoms and some negative symptoms of schizophrenia.  Increased 5-HT2A receptor activity has been implicated in schizophrenia, contributing to disturbances in perception and thought processes, which are hallmark symptoms of psychosis. GABA Receptors Normal Brain:GABA (gamma- aminobutyric acid) is the primary inhibitory neurotransmitter in the brain, regulating excitatory activity. The main GABA receptors are GABA-A and GABA-B. Proper GABAergic functioning is crucial for controlling excitatory signals and maintaining the balance between excitation and inhibition. GABA Receptors  Schizophrenia:Evidence suggests reduced GABAergic activity, particularly in certain brain regions like the prefrontal cortex. This GABAergic dysfunction may contribute to disorganized thinking and cognitive impairments in schizophrenia.  Dysfunction in GABA receptors, in conjunction with NMDA receptor hypofunction, may lead to the disruption of neural circuits that are crucial for working memory and attention. Acetylcholine Receptors Normal Brain:Acetylcholine, through nicotinic (nAChR) and muscarinic (mAChR) receptors, plays a role in attention, learning, and memory. Nicotinic receptors are implicated in cognitive processes and synaptic plasticity. Acetylcholine Receptors Schizophrenia:In schizophrenia, nicotinic receptor dysfunction (especially reduced α7 nicotinic receptor activity) has been associated with cognitive deficits, including impairments in attention and memory. The cholinergic hypothesis of schizophrenia suggests that targeting muscarinic receptors (especially M1 and M4 subtypes) could potentially improve cognitive symptoms. Histamine Receptors Normal Brain:Histamine receptors, particularly H1 and H3 receptors, play roles in wakefulness, cognition, and appetite regulation. Histamine Receptors  Schizophrenia:Altered histamine signaling, particularly through H1 receptors, may contribute to disturbances in arousal and cognition observed in schizophrenia.  Some atypical antipsychotics have histamine receptor activity, which may influence side effects like sedation and weight gain, rather than directly addressing core symptoms. Dopamine Hypothesis​ The dopamine hypothesis is one of the most widely accepted explanations for schizophrenia, especially for the positive symptoms (hallucinations, delusions).​ Schizophrenia is caused by an overactivity of dopamine in certain brain pathways, particularly in the mesolimbic pathway, Dopamine Hypothesis​ Antipsychotic medications, which block dopamine receptors (D2 receptors), reduce positive symptoms.​ Stimulants like amphetamines, which increase dopamine levels, can induce psychotic symptoms in healthy individuals.​ Glutamate Hypothesis The glutamate hypothesis suggests that schizophrenia is linked to dysfunction in the brain’s glutamate system, particularly at NMDA receptors.​ A hypofunction of NMDA glutamate receptors leads to abnormal neurotransmission, contributing to the development of schizophrenia.​ Glutamate Hypothesis Drugs like PCP (phencyclidine) and ketamine, which block NMDA receptors, can induce schizophrenia-like symptoms, including both positive and negative symptoms.​ Post-mortem studies have shown alterations in glutamate levels and receptor binding in the brains of people with schizophrenia.​ Serotonin Hypothesis​ The serotonin hypothesis is based on the idea that abnormalities in serotonin neurotransmission also contribute to schizophrenia.​ ​ An imbalance in serotonin, particularly overactivity at serotonin 5-HT2A receptors, may contribute to both positive and negative symptoms of schizophrenia.​ Serotonin Hypothesis​ Atypical antipsychotics like clozapine and risperidone, which block serotonin receptors as well as dopamine receptors, are effective in treating schizophrenia.​ Hallucinogenic drugs like LSD, which activate serotonin receptors, can cause symptoms similar to schizophrenia.​ Neurodevelopmental Hypothesis​  This hypothesis focuses on early brain development, suggesting that schizophrenia arises from abnormal brain development before or around birth.​ ​  Genetic or environmental factors (e.g., maternal infections, malnutrition, or complications during birth) during early brain development cause subtle brain abnormalities that later manifest as schizophrenia.​ Neurodevelopmental Hypothesis​ Studies have found structural brain abnormalities (e.g., enlarged ventricles, reduced gray matter) in individuals with schizophrenia.​ Prenatal exposure to infections or stress is linked to an increased risk of developing schizophrenia.​ Genetic Hypothesis​ Schizophrenia has a strong genetic component, though no single gene is solely responsible for the disorder.​ Schizophrenia results from a complex interaction of multiple genetic factors that increase an individual’s vulnerability to the disorder.​ Genetic Hypothesis​ Family, twin, and adoption studies show that schizophrenia runs in families, with a higher concordance rate in monozygotic (identical) twins.​ Genome-wide association studies (GWAS) have identified multiple risk genes, including those involved in dopamine, glutamate, and immune system functionin Environmental Hypothesis​ Environmental factors are believed to interact with genetic vulnerabilities to increase the risk of schizophrenia.​ Various environmental factors, particularly during early life and adolescence, contribute to the onset of schizophrenia, often in genetically predisposed Environmental Hypothesis​ Prenatal factors such as maternal stress, infections, malnutrition, and complications during birth are associated with increased risk.​ Childhood trauma, urban upbringing, cannabis use during adolescence, and social stress are environmental factors linked to a higher likelihood of developing schizophrenia.​ Immune and Inflammatory Hypothesis​ Emerging research suggests that inflammation and immune system dysfunction may play a role in schizophrenia.​ ​ Schizophrenia could be related to an overactive or dysregulated immune response, possibly leading to chronic inflammation that affects brain development and function.​ Immune and Inflammatory Hypothesis​ Increased levels of inflammatory markers, such as cytokines, have been found in individuals with schizophrenia.​ Some studies suggest that autoimmune diseases or prenatal infections may increase the risk of schizophrenia.​ Psychosocial Hypothesis​ Psychological and social factors, including stress, family dynamics, and trauma, are believed to influence the development of schizophrenia.​ ​ Schizophrenia may result from the interaction of genetic vulnerability with stressful life events, poor family relationships, Psychosocial Hypothesis Stress, particularly during adolescence, can trigger psychotic episodes in individuals at risk.​ Psychodynamic theories suggest that dysfunctional family environments or communication patterns may contribute to the development of the disorder.​ Social defeat, isolation, and minority status are linked to a higher risk of schizophrenia​ Diagnostic and Statistical Manual of Mental Disorders (DSM–5) Two or more of the following symptoms for at least 1 month; one symptom should be either 1, 2, or 3: ◦ (1) delusions ◦ (2) hallucinations ◦ (3) disorganized speech ◦ (4) disorganized (catatonic) behavior ◦ (5) negative symptoms (diminished motivation or emotional expression) Functioning in work, relationships, or self-care has declined since onset © 2015 John Wiley & Sons, Inc. All rights reserved. DIFFERENTIAL DIAGNOSES Differential diagnoses that need to be considered are as follows:  Bipolar I Disorder with psychotic features  Delusional Disorders  Schizoaffective Disorder  Brief Psychotic Disorder DIFFERENTIAL DIAGNOSES  Psychosis NOS (Not Otherwise Specified)  Certain personality disorders  Drug and medication induced psychosis Bipolar disorder People with bipolar disorder experience intense emotional states that typically occur during distinct periods of days to weeks, called mood episodes  These mood episodes are categorized as manic/hypomanic (abnormally happy or irritable mood) or depressive (sad mood)  People with bipolar disorder generally have periods of neutral mood as well. When treated, people with bipolar disorder can lead full and productive lives.  Delusional disorder person has a variety of paranoid [feeling extremely nervous and worried because he believes that other people do not like him or are trying to harm him]beliefs, but these beliefs are usually not bizarre and are not accompanied by any other symptoms of schizophrenia. For example, a person who is functioning well at work but becomes unreasonably convinced that his or her spouse is having an Schizoaffective disorders Characterized by recurring episodes of mood/affective symptoms and psychotic symptoms  Mood symptoms maybe manic, depressive or both manic and depressive Psychotic symptoms may occur before, during or after their depressive, mixed or manic episodes The illness tends to be difficult to diagnose since the symptoms are similar to other disorders with prominent mood and psychotic symptoms like bipolar disorder with Brief Psychotic Disorders There is presence of one or more of the following symptoms: Delusions, Hallucinations, Disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior similar to schizophrenia The duration of an episode is at least 1 day but less than 1 month and with eventual full return to premorbid level of functioning. Psychoses NOS (Not Otherwise Specified) Here the patient has psychotic symptoms but does not qualify for any of the other categories  Personality disorder three personality disorders that need to be considered in the differential diagnosis (a) Schizotypal personality disorder is characterized by a pervasive pattern of discomfort in close relationships with others, along with the presence of odd thoughts and behaviors. The oddness in this disorder is not as extreme as that observed in schizophrenia (b) Schizoid personality disorder the person has difficulty and lack of Substance abuse Substance abuse (eg, abuse of alcohol, cocaine, opiates, psycho stimulants, or hallucinogens) often leads to disturbed perceptions, thought, mood, and behavior. The anabolic steroids used by body builders and athletes can lead to psychotic symptoms3. Anticholinergic medications can lead to delirium, especially if abused. Substance abuse Many prescribed medications have been associated with mental status changes, especially the following  Corticosteroids (psychosis or mania)  Levodopa (hallucinations or insomnia)  Antidepressants (mania)  Beta blockers (depression) Sibutramine, an anti obesity medication, (contained in many slimming products) is often used by patients to lose weight. A history of use of slimming pills should always Psychoses secondary to organic causes (a) Metabolic illnesses  (i) Wilson disease (hepatolenticular degeneration), an autosomal recessive illness is a disorder of the metabolism of copper. The first symptoms are often vague changes in behavior during adolescence, which are followed by the appearance of odd movements.  (ii) Porphyria is a disorder of heame biosynthesis that can present as psychiatric symptoms. The psychiatric symptoms may be associated with electrolyte changes, peripheral neuropathy, and episodic severe abdominal pain. Psychoses secondary to organic causes (iii) Hypoxemia or electrolyte disturbances may present with confusion and psychotic symptoms (iv) Hypoglycemia can produce confusion and irritability and may be mistaken for psychosis (b) Delirium  Delirium from whatever cause (eg, metabolic or endocrine disorders) is an important condition to consider, especially in the elderly or hospitalised patient. Although patients with delirium may have a wide range of neuropsychiatric abnormalities, the clinical hallmarks are decreased attention span and a waxing-and- waning type of confusion. (c) Endocrine disorders Thyroid illness may be confused with schizophrenia. Severe hypothyroidism or hyperthyroidism can be associated with psychotic symptoms. Hypothyroidism is usually associated with depression, which if severe may be accompanied by psychotic symptoms. A hyperthyroid person is typically anxious, and irritable. (c) Endocrine disorders Both adrenocortical insufficiency (Addison disease) and hypercortisolism (Cushing syndrome) may result in mental status changes Most patients with Cushing syndrome will have a history of long-term steroid therapy for a medical illness. (d) Infectious illnesses Many infectious illnesses, such as influenza, Lyme disease, hepatitis C, s can cause mental status changes such as depression, anxiety, irritability, or psychosis. Elderly people with pneumonias or urinary tract infections may become confused or frankly psychotic. The infectious illnesses of particular interest are the following: Neurosyphilis, HIV infection, Cerebral abscess (e) Heavy metal toxicity Heavy metal toxicity may cause changes in personality, thinking, or mood. Occupational exposure is the usual source of heavy metal toxicity, but cases have also resulted from ingestion of herbal medications contaminated with heavy metals. Antipsychotic Drugs Antipsychotic drugs, also known as neuroleptics or major tranquilizers, are medications primarily used to treat psychosis, including disorders such as schizophrenia, bipolar disorder, and severe depression with psychotic features. They are designed to reduce or manage symptoms such as hallucinations, delusions, disordered thinking, and severe mood swings. Mechanism of Action Antipsychotics primarily target neurotransmitter systems in the brain, particularly dopamine and serotonin, to modulate mood, thought processes, and behavior. Classes of Antipsychotic Drugs  Typical (First-Generation) Antipsychotics (FGAs)  Introduced in the 1950s, typical antipsychotics primarily block dopamine D2 receptors.  They are effective at reducing positive symptoms of schizophrenia (hallucinations, delusions) but often have limited efficacy on negative symptoms (emotional flatness, lack of motivation) and cognitive impairments.  FIRST-GENERATION ANTIPSYCHOTIC  (low potency)  Chlorpromazine  Thioridazine  FIRST-GENERATION ANTIPSYCHOTIC  (high potency)  Fluphenazine  Haloperidol  Loxapine  Molindone  Perphenazine  Pimozide  Prochlorperazine  Thiothixene  Triuoperazine Mechanism of Action  Dopamine D2 receptor blockade: FGAs exert their antipsychotic effects by binding to and blocking dopamine D2 receptors, particularly in the mesolimbic and mesocortical pathways.  Mesolimbic pathway: Dopamine blockade here helps reduce positive symptoms (hallucinations, delusions).  Nigrostriatal pathway: Dopamine blockade in this pathway leads to extrapyramidal side effects (EPS) such as tremors, rigidity, and bradykinesia.  Tuberoinfundibular pathway: Blockade of dopamine in this pathway can increase prolactin levels, leading to side effects such as galactorrhea, gynecomastia, and sexual dysfunction. Side Effects of FGAs  Extrapyramidal Symptoms (EPS)  Parkinsonism: Tremors, bradykinesia, and muscle rigidity resembling Parkinson's disease.  Dystonia: Involuntary muscle contractions, often affecting the neck, jaw, and eyes.  Akathisia: A sense of restlessness and an inability to stay still, which can be very distressing for patients.  Tardive Dyskinesia (TD): Involuntary, repetitive movements, particularly of the face, tongue, and limbs. TD is a potentially irreversible side effect of long-term antipsychotic use. What causes extrapyramidal symptoms? Extrapyramidal system is a neural network in brain that helps regulate motor control and coordination. It includes the basal ganglia, a set of structures important for motor function. The basal ganglia need dopamine for proper function. Side Effects of FGAs Sedation and Anticholinergic Effects More common with low-potency FGAs like chlorpromazine. Anticholinergic effects: Dry mouth, blurred vision, constipation, urinary retention. Sedation: Common in low- potency agents, which can be problematic in daily functioning. Side Effects of FGAs  Prolactin Elevation  Dopamine blockade in the tuberoinfundibular pathway can lead to increased prolactin levels, causing: ◦ Galactorrhea (milk production) ◦ Gynecomastia (breast enlargement in males) ◦ Amenorrhea (loss of menstrual periods) ◦ Sexual dysfunction (reduced libido, erectile dysfunction)  High-potency FGAs like haloperidol and fluphenazine are more likely to cause prolactin-related side effects. Side Effects of FGAs  Tardive Dyskinesia (TD)  A late-onset, often irreversible movement disorder characterized by repetitive, involuntary movements of the face, lips, and limbs.  Risk increases with the duration of antipsychotic use and higher doses.  Management: Reducing or discontinuing the antipsychotic, switching to an atypical antipsychotic, and using TD-specific treatments like valbenazine. Side Effects of FGAs  Neuroleptic Malignant Syndrome (NMS)  A rare but life-threatening condition associated with the use of antipsychotics.  Symptoms include high fever, muscle rigidity, autonomic dysfunction (unstable blood pressure, sweating), and altered mental status.  Treatment: Discontinuation of the antipsychotic, intensive supportive care, and administration of dantrolene or bromocriptine. Advantages and Limitations of FGAs  Advantages:  Effective for positive symptoms: FGAs are highly effective in treating positive symptoms like hallucinations, delusions, and agitation.  Cost-effective: Many FGAs are available in generic forms, making them more affordable.  Long-acting injectable formulations: Certain FGAs (e.g., haloperidol, fluphenazine) are available in depot formulations, improving medication adherence in patients with poor compliance. Advantages and Limitations of FGAs  Limitations:  Limited efficacy for negative and cognitive symptoms: FGAs are less effective in treating negative symptoms (e.g., lack of motivation, emotional blunting) and cognitive impairments in schizophrenia.  High risk of movement disorders (EPS and TD): Long-term use of FGAs is associated with a high risk of tardive dyskinesia and other movement-related side effects.  Prolactin-related side effects: Elevated prolactin levels can lead to sexual dysfunction and other endocrine disturbances.  Sedation and anticholinergic effects: Low- potency FGAs can cause significant sedation and anticholinergic side effects, which may limit their use. Atypical (Second-Generation) Antipsychotics (SGAs)  Introduced in the 1990s, atypical antipsychotics target both dopamine (D2) and serotonin (5-HT2A) receptors.  SGAs are effective at treating both positive and negative symptoms and have a lower risk of causing EPS and TD compared to FGAs.  They carry their own set of side effects, particularly metabolic syndrome (weight gain, diabetes, lipid abnormalities). SECOND-GENERATION ANTIPSYCHOTIC (atypical antipsychotic)  SECOND-GENERATION ANTIPSYCHOTIC  (atypical antipsychotic)  THIRD-GENERATION ANTIPSYCHOTICS  Risperidone  Ziprasidone  Paliperidone  Iloperidone  Lurasidone  Olanzapine  Quetiapine  Clozapine  Asenapine Common SGA  Clozapine (Clozaril): The most effective antipsychotic for treatment-resistant schizophrenia but requires regular blood monitoring due to the risk of agranulocytosis.  Risperidone (Risperdal): Effective at treating both positive and negative symptoms but may still cause EPS at higher doses and increases prolactin levels.  Olanzapine (Zyprexa): Highly effective for psychosis but associated with significant weight gain, sedation, and metabolic disturbances. Common SGA Quetiapine (Seroquel): Often used for both schizophrenia and bipolar disorder; has sedative effects and a lower risk of EPS but can cause weight gain. Aripiprazole (Abilify): A partial dopamine agonist, meaning it modulates rather than completely blocks dopamine activity. It has a lower risk of weight gain and metabolic syndrome but may cause restlessness (akathisia). Common SGA Ziprasidone (Geodon): Lower risk of weight gain but requires dosing with food for optimal absorption. Lurasidone (Latuda): Has a favorable metabolic profile and is effective in treating both schizophrenia and bipolar depression. SGA Metabolic Side Effects: Weight gain: Particularly with olanzapine and clozapine. Increased risk of diabetes: Due to effects on insulin sensitivity. Lipid abnormalities: Elevated cholesterol and triglycerides. SGA Sedation SGAs like quetiapine, olanzapine, and clozapine can cause significant sedation, which may be therapeutic in some cases (for patients with agitation or insomnia) but problematic Long-acting injectables are formulations of antipsychotics that are administered every 2 to 12 weeks, depending on the drug. Examples: ◦ Haloperidol Decanoate (FGA) ◦ Risperidone LAI (SGA) ◦ Aripiprazole LAI (SGA) ◦ Paliperidone Palmitate (SGA) Third-generation antipsychotics (TGAs) Third-generation antipsychotics (TGAs) represent a newer class of drugs that aim to improve upon the efficacy and side effect profile of both first-generation (typical) and second- generation (atypical) antipsychotics. MOA TGAs primarily act as partial agonists at dopamine D2 receptors, meaning they activate the receptor, but only partially, thus preventing over- activation or complete blockade. This unique action allows TGAs to balance dopamine levels in various brain regions Third-generation antipsychotics (TGAs) Aripiprazole Brexpiprazole Cariprazine Side Effects of TGAs TGAs have a more favorable side effect profile compared to both FGAs and SGAs, they still carry some risks 1. Extrapyramidal Symptoms (EPS) 2. Metabolic Side Effects 3. Prolactin Elevation less common with TGAs compared to many FGAs&SGAs Receptor Type Effect Associated Drugs Therapeutic for Most FGAs, positive symptoms, D2 (Dopamine) Risperidone, but causes EPS and Olanzapine hyperprolactinemia Reduces EPS, treats Most SGAs (Clozapine, 5-HT2A (Serotonin) both positive and Olanzapine, negative symptoms Quetiapine) Clozapine, Olanzapine, H1 (Histamine) Sedation, weight gain Quetiapine Anticholinergic effects, M1 (Muscarinic) Clozapine, Olanzapine reduced EPS Orthostatic Clozapine, Quetiapine, Alpha-1 Adrenergic hypotension Risperidone Anxiolytic, mood- 5-HT1A (Serotonin) Aripiprazole stabilizing Pharmacokinetic of anti psychotic drugs Pharmacokinetics (PK) of antipsychotic drugs refers to the processes by which these drugs are absorbed, distributed, metabolized, and excreted by the body.. Absorption Oral Absorption: Most antipsychotics are well absorbed after oral administration  Extent of absorption can be influenced by the drug’s formulation and gastrointestinal factors Bioavailability Many antipsychotics have relatively low oral bioavailability (e.g., around 20-40%) due to extensive first-pass metabolism in the liver. Exceptions include some long- acting injectable forms that bypass gastrointestinal absorption. Volume of Distribution (Vd) Volume of Distribution (Vd): Antipsychotic drugs tend to have a large volume of distribution because they are highly lipophilic, allowing them to penetrate into tissues, including the brain.  This large Vd can result in a longer duration of action. Protein Binding Most antipsychotics are highly bound to plasma proteins (typically 90-95%). This influences the free (active) drug available to exert therapeutic effects or side effects. Metabolism  Hepatic Metabolism: Antipsychotics are primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, particularly CYP3A4, CYP2D6, and CYP1A2.  This can result in variable drug levels due to genetic polymorphisms in these enzymes, drug interactions, or liver impairment. Active Metabolites: Some antipsychotics, like risperidone, are metabolized into active compounds (e.g., 9- hydroxyrisperidone or paliperidone), which can contribute to the overall therapeutic effects or side effects. Excretion Elimination Half-life: Antipsychotics generally have long half-lives, ranging from 12 to over 100 hours, depending on the drug and formulation.  This allows for once-daily dosing for most oral formulations. Renal and Biliary Excretion: The majority of antipsychotics are excreted in the urine and feces after hepatic metabolism. Kidney function does not significantly affect the clearance of most antipsychotics, except for certain drugs with active renal excretion, like paliperidone.