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Antipsychotics play a pivotal role in treating various psychiatric conditions, such as schizophrenia, bipolar disorder, and other psychotic disorders. The first antipsychotic was discovered in 1959 and today there are two generations of antipsychotics, allowing clinicians to identify the best therapy for each patient. 

Current FDA-approved first-generation antipsychotics include haloperidol, chlorpromazine, fluphenazine, perphenazine, and thioridazine. Second-generation antipsychotics, also known as atypical antipsychotics include risperidone, olanzapine, quetiapine, aripiprazole, and clozapine. Typical antipsychotics work by inhibiting dopaminergic neurotransmission. Additionally, typical antipsychotics also affect serotonin, histamine, acetylcholine, and norepinephrine systems. 

Atypical antipsychotics has diversity among agents in terms of their efficacy as well as their motor- and endocrine-related side effects and are categorized on the concept of spectrum atypia. The spectrum ranges from the least atypical agent to the most atypical across three levels.  

This proposed spectrum starts with dopamine (D2) and serotonin 5-HT2A and C receptors at Level 1, which are shared targets among all atypical antipsychotics, through muscarinic (M1) receptors and glycine transporter activity (GlyT) . Level 1 and level 2 agents involve additional targets like histaminergic (H1) and alpha receptors, along with brain-derived neurotrophic factor (BDNF). 

This difference in efficacy and side effects of atypical are based on their affinity for serotonergic 5HT2A/D2 and 5HT2C/D2 receptors, as well as their fast dissociation from the D2 receptor compared to typical antipsychotics. 
Differentiating antipsychotics as typical versus atypical is based primarily on their adverse effects. Atypicality denotes antipsychotics with lower risks of motor-related adverse effects or extrapyramidal symptoms and hyperprolactinemia compared to typical antipsychotics. 

Extrapyramidal symptoms include dystonia, akathisia, Parkinsonism, and tardive dyskinesia. These symptoms can be very stigmatizing for patients and may require additional treatment.  

Symptoms of akathisia may include restlessness, trouble standing still, pacing  the floor, and a constant rocking back-and-forth of the feet.  
Symptoms of acute dystonia may involve facial grimacing, involuntary eye movements, abnormal posture, and muscle spasms, especially of the tongue, face, neck, and back. 

Pseudoparkinsonism symptoms include stooped posture, shuffling gait, tremors at rest, rigidity of skeletal muscles, and bradykinesia or slow movements. 

Tardive dyskinesia can persist even after stopping medications and involves protrusion and rolling of the tongue, a chewing motion, sucking and smacking of the lips, and facial dyskinesia -  involuntary and repetitive movements of the mouth and face. 

Both typical and atypical agents carry the risk of neuroleptic malignant syndrome, a rare but potentially fatal condition characterized by symptoms such as rigidity, tremors, fever, and altered mental status.  Antipsychotics also have warnings for cardiotoxic effects such as QTc prolongation and arrhythmias, potential for seizures and increased mortality risk in older individuals with dementia.  Lastly, clozapine increases the risk of agranulocytosis and myocarditis in patients.  

Crucial for antipsychotic effectiveness in schizophrenia and other psychiatric disorders is blocking of striatal dopamine D2 receptors for symptom relief, especially positive symptoms. Dopamine plays a critical role in schizophrenia, a psychiatric disorder characterized by positive symptoms of hallucinations and delusions and by negative symptoms of apathy and cognitive impairment. 

Reduced cortical dopamine release is linked to cognitive impairment and negative symptoms, while abnormalities or excess in striatal dopamine contribute to positive symptoms. 

Studies show that achieving dopamine D2 receptor blockade above 50% occupancy is crucial for a higher chance of clinical response. Thus, the target therapeutic range is between 60% and 80% occupency however extrapyramidal symptoms are seen when occupancy exceeds approximately 85%. Currently, only clozapine and aripiprazole, a partial dopamine agonist, are the exceptions to this pattern.

While typical agents primarily target positive symptoms through dopamine D2 receptor blockade, atypical antipsychotics have broader efficacy than typical antipsychotics due to their diverse mechanisms of action and ability to target multiple receptors. Additionally, neurotrophin may lead to synaptic plasticity in the brain over time. Atypical antipsychotics are better suited for treating various psychiatric symptoms including positive, negative, mood, and suicidal symptoms. 

For atypical agents such as olanzapine and clozapine, which carry greater risk for metabolic syndrome , clinicians are encouraged to look for ways to prevent or reduce these effects by recommending physical exercise and dietary changes. Clinicians are also encouraged to weigh both the benefits and tolerability of these medications.  Individualized treatment should rely on careful clinical observation and assessment.

Emerging treatment options based on pharmacogenetic tests or biomarkers may hold promise for personalized antipsychotic selection; however, their implementation remains limited.