Antipsychotics and Schizophrenia Notes
PS 333 / NE 333: Antipsychotics
Characteristics of Schizophrenia
Definition: Schizophrenia is defined as an umbrella term for mental disorders characterized by a distortion of reality.
Prevalence: It affects approximately 1% of the population.
Characteristic Symptoms
Psychotic Symptoms (Positive Symptoms)
Delusions: Beliefs about the world that contradict accepted reality, persist despite evidence to the contrary.
Hallucinations: Perceptions without external stimuli, with verbal-auditory hallucinations being the most common type.
These can include difficulty distinguishing between one’s verbalized thought and external speech.
Disorganized Speech:
Derailment: Example - "I always liked geography. My last teacher in that subject was Professor August A. He was a man with black eyes. I also like black eyes. There are also blue and grey eyes and other sorts, too…"
Word Salad: Example - "Oh, it [life in a hospital] was superb, you know, the trains broke, and the pond fell in the front doorway."
Negative Symptoms
Symptoms include:
Flat Affect: Diminished emotional expression.
Reduced Motivation: Lack of drive or initiative.
Social Withdrawal: Retreating from social interactions.
Often diagnosed as other disorders, such as depression.
Cognitive Symptoms
Symptoms include:
Difficulty Processing Information: Impaired ability to make decisions and process information.
Attention and Focus Problems: Difficulty maintaining attention and focus.
Memory Impairment: Problems with working memory and recalling information.
Patients may display concrete thinking, indicating difficulties with figurative language.
Proverb interpretation is a common method for clinical assessment and diagnosis.
Time Course of Symptoms
Symptoms most often begin during the late teenage years and early twenties.
Etiology of Schizophrenia
The exact cause of schizophrenia remains not clearly understood.
Research suggests that animal models do not fully capture the essential features of the disorder.
Multiple phenotypes indicate that schizophrenia may consist of multiple disorders.
Many diverse risk factors include genetic, environmental, and developmental components.
Antipsychotics Treatment
Historical Treatments before Antipsychotics:
Electroshock therapy
Insulin coma
Frontal lobotomy
First Generation Antipsychotics (Typical Antipsychotics/Neuroleptics)
Emerged in the 1950s, with Chlorpromazine (Thorazine) being one of the first.
Developed initially as an antihistamine and subsequently found to act as a tranquilizer, its effects on psychotic symptoms were discovered serendipitously.
Known as a "dirty drug", Chlorpromazine acts as an antagonist at multiple receptor types, including:
Histamine receptor
Dopamine receptor
Serotonin receptor
Adrenergic receptor
Cholinergic receptor
Other examples: Haloperidol, which similarly acts on multiple receptor types.
Mechanism of Action
Typical Antipsychotics: These medications primarily act as dopamine (DA) receptor antagonists.
The clinical dose required for the drug is proportional to its potency in blocking the D2 receptor.
Dopamine Hypothesis: This theory posits that excess dopamine function can result in the positive symptoms associated with schizophrenia.
Drugs that increase dopamine signaling, such as Amphetamine and L-DOPA, can induce psychosis.
Strong correlations exist between D2 receptor blockade and the reduction of schizophrenic symptoms.
Effectiveness of Antipsychotics
Antipsychotics have demonstrated effectiveness in managing positive symptoms of schizophrenia, but patient responses vary:
1/3 of patients respond well to treatment.
1/3 show some improvement.
1/3 fail to respond.
Negative and cognitive symptoms tend to be more resistant to treatment.
Side Effects
Blocking dopamine receptors can lead to significant side effects:
Parkinsonism: Treated by reducing excess acetylcholine activity; antipsychotics may be combined with anticholinergic agents like Benztropine.
Tardive Dyskinesia (TD): Characterized by involuntary and repetitive movements, notably in the face and jaw. The incidence of TD increases with the duration of treatment.
Endocrine Dysregulation.
Unpleasant side effects often cause many patients to discontinue treatment, leading to potential relapse.
Second-Generation Antipsychotics
Introduced in the 1990s, these drugs have additional targets beyond dopamine receptors, acting as antagonists to serotonin, noradrenaline, and/or acetylcholine receptors.
Example: Clozapine, which can reduce positive symptoms with fewer motor side effects like TD and parkinsonism.
Genetics of Schizophrenia
Genetic studies identify potential therapeutic targets for schizophrenia treatment, emphasizing:
No single gene or mutation solely causes schizophrenia, though multiple risk-associated genes have been identified.
Variations in acetylcholine (Ach) receptor types, such as muscarinic receptors (M1-M5) and several nicotinic receptor subtypes, may contribute to the disorder.
The CHRNA7 gene mutation related to the α7-nicotinic receptor is recognized as a risk factor for schizophrenia.
Nicotine as an agonist may alleviate some negative and cognitive symptoms, leading patients to self-medicate, as they exhibit the highest smoking prevalence, extracting more nicotine per cigarette.
Novel ACh receptor therapies are being developed aiming at reducing cognitive and negative symptoms.
Quiz Introduction
Reflect on the mechanism of amphetamine in terms of dopamine packaging, asking: Which target of amphetamine is responsible for packaging dopamine into neurotransmitter vesicles for release?
a. the dopamine autoreceptor
b. the D1 dopamine receptor
c. vesicular monoamine transporter (VMAT)
d. dopamine transporter (DAT)
These notes synthesize information from the lecture on antipsychotics and schizophrenia, covering symptoms, treatment options, effectiveness, side effects, and genetic considerations.