The Best Antipsychotic Medication in The World 


I’ve said it before in previous videos, older medications are more effective and newer medications have fewer side effects. 

The advent of SSRIs in the late 1980’s and early 1990’s was largely driven by safety and not efficacy. The same is true for antipsychotic medications. This may be the reason most people haven’t even heard about Clozapine (brand name Clozaril). 


Clozapine is the single most effective antipsychotic available, and it works in treatment resistant schizophrenia where no other medication is proven to be effective. 

The results speak for themselves, 30% of previously treatment resistant patients experience symptom reduction within 6 weeks and that number jumps to 60% after 6 months of treatment. 

Clozapine has a slew of additional benefits including mood stabilizing prosperities (it can be used in bipolar disorder), reduction in psychogenic polydipsia and the hyponatremia associated with it, reduction in hostility and aggression, reduction in the risk of suicidal ideation, improvement in substance use, and it may even help patients quit smoking a difficult task in schizophrenia. 

So why are most schizophrenic patients not on this medication if it’s so great? 

Side effects, side effect, side effects

-Sedation: feeling tired this can largely be mitigated by dosing the medication at night before bedtime. 

-Tachycardia: It’s worth getting an EKG in patients with preexisting heart conditions or those at high risk due to hypertension and hyperlipidemia 

-Sialorrhea: excessive saliva production leading to drooling, no one wants this 


-Constipation: this should be addressed immediately if a patient complains about it as it can lead to serious complications. In many cases Senna and Colace will do the trick

-Orthostatic hypotension 

-Weight gain 

Serious and potentially fatal Side effects include: 

-Agranulocytosis: decreased absolute neutrophil count which can result in increased risk for serious infection and the reason everyone on the medication gets weekly blood draws for the first 6 months 

-Seizures: clozapine is known to lower the seizure threshold 

-Myocarditis: inflammation of the heart usually due to a viral infection 

The risk for agranulocytosis is highest when starting treatment, usually during the first year of treatment (0.8%) and the maximum risk is between 4 and 18 weeks (when 77% of cases occur), although it can still occur at any point in the treatment.


Monitoring is thus very important, and each patient must be registered in the Risk Evaluation and Mitigation strategy (REMS) data base before starting the medication. 

A CBC with differential must be drawn to calculate the absolute neutrophil count prior to starting treatment and then weekly for the first 6 months. Then monitoring continues every 2 weeks for the next 6 months and finally monthly after the first year of treatment. 

If agranulocytosis occurs stopping clozapine allows majority of cases to recover within 14 days. 

Now that we know that this medication is very effective but comes with a high side effect burden a natural next question might be why does the medication work? 

Mechanism of Action

Clozapine has very low affinity for the D2 receptors which is unique as most other antipsychotics will bind strongly to D2 receptors. Clozapine had far greater D1 and D4 binding affinity, blocking both receptors. 

Clozapine also has significant activity at other neurotransmitter sites. It blocks alpha receptors which may be the reason for orthostatic hypotension. It blocks histamine H1 receptors resulting in sedation and weight gain. It blocks 5-HT2A serotonin receptors and is highly anticholinergic resulting in constipation and urinary retention. 

It has two unique properties; it influences the glutamate system by altering NMDA receptor sensitivity and increases the release of brain derived neurotrophic factor BDNF. 

Metabolism And Drug Interactions

Clozapine is primarily metabolized by CYP450 1A2 and 3A4 and cigarette smoking will cause a reduction in clozapine levels due to induction of CYP 1A2. 

Before Starting the Medication

Before starting clozapine, the ANC must be above 1,500. If neutropenia develops treatment will depend on the severity of the drop. 

Mild Neutropenia: ANC 1,000-1,499, you would continue treatment and check an ANC three times weekly until it reaches 1,500. 

Moderate Neutropenia: ANC between 500 and 999, stop treatment and check the ANC daily until it reaches 1,000 then 3 times weekly until it reaches 1,500 then weekly for 4 weeks before returning to the patients prior monitoring schedule. 

Severe Neutropenia: ANC less than 500, stop treatment and check an ANC daily until it’s 1,000 then 3 times weekly until it’s 1,500. The patient should not be rechallenged without a hematology consult and clear benefits that outweigh the risks. 


Clozapine can be started at 12.5 to 25 mg at bedtime. The dose can be increased 25 mg/day inpatient and 25 mg per week in the outpatient setting as tolerated. 

You can overlap prior treatment with another antipsychotic and tapper the old medication once clozapine dose reaches 100 mg or more. 

Plasma Levels

Clozapine dose should be based on serum levels, with a target blood level of 200 to 300 ng/ml. If there are still symptoms present the target serum level is 450 ng/ml. There are no benefits to serum levels above 900 ng/ml. 

Hey Doc, What’s Psychogenic Polydipsia?

This is one of the interesting occurrences that can present on the medical floors, emergency rooms, or inpatient units. 

A patient comes in with an established diagnosis of schizophrenia and is currently taking ziprasidone. The person is constantly asking for glasses of water and drinking water excessively throughout the day. 

You might be thinking what is the harm in drinking water, isn’t staying hydrated a healthy behavior? 

…But you order a basic metabolic panel and find the persons sodium is 125 mEq/L. 

Now the panic sets in, it’s time to worry and the patient continues to complain of feeling thirsty and is noted to be urinating frequently. 

There are a few possibilities for the persons behavior, but we need to consider psychogenic polydipsia or primary polydipsia. This was first described in the 1930s in patients with schizophrenia who drank water excessively resulting in low serum sodium levels. 

The cause is unknown, but these patients may have an acquired defect in the hypothalamic thirst regulation. Medications have also been associated with worsening of psychogenic polydipsia. It’s thought to be related to the anticholinergic effects of many of these medications. Examples include carbamazepine, chlorpromazine, oxcarbazepine, haloperidol, and valproate. 

Psychogenic polydipsia (PP) is common, and it’s usually associated with schizophrenia but can occur in other psychotic, mood, and anxiety disorders. Some users of MDMA also develop PP. 

PP is a primary problem where the patient is drinking too much water. This results in a dilution of the blood and thus a low sodium level (defined as < 135 mEq/L) and low serum osmolality. The urine will also be dilute < 100 mOsmol/kg with low urine sodium. 

Two other potential places where we can see polyuria are in cases of hyperglycemia from uncontrolled diabetes and nephrogenic diabetes insipidus. The key distinction in the first case is hyperglycemia. The water is drawn out by osmotic diuresis secondary to excess glucose in the urine. The key labs here are a fasting glucose and a urine analysis which should show hyperglycemia and glucose in the urine. In nephrogenic diabetes insipidus the brain secretes ADH just fine, but the kidney does not respond to it. The urine will be dilute, but the serum sodium level will be high not low separating it from psychogenic polydipsia.

Treatment includes fluid restriction to 1000-1500 mL/day, this can be difficult to enforce even on an inpatient unit. The person may need to be watched because sources like the bathroom sink or even toilet may be used to consume more water. This is usually enough of a treatment, but should the sodium remain low you can add sodium chloride tablets 1-3 grams daily. 

In severe cases where the sodium drops below 120 the person can have a seizure. In these cases, it’s best to handle the fluid replenishment on the medical floor with 3% saline. 

You must be careful not to correct the sodium too rapidly as it can result in the dreaded central pontine myelinolysis which can result in quadriparesis. That’s why we correct the sodium at a rate of no more than 10 mmol/L/24 h or 0.5 mEQ/L/h 

Most Commonly Prescribed Psychiatric Medications: Hydroxyzine/Vistaril

  • Hydroxyzine is a medication I’m very familiar with, it’s used as an as needed medication for anxiety and insomnia on my inpatient unit. 
  • Hydroxyzine is a histamine receptor antagonist or antihistamine with anticholinergic properties like diphenhydramine. 
  • It’s FDA approved for several things, but my favorite is anxiety and tension associated with psychoneurosis. Several other indications include anxiety associated with organic disease states, premedication sedation, and anxiety withdrawal symptoms in alcohol use disorder. 
  • The mechanism is very simple it blocks histamine H1 receptors, not much else to say about it.  
  • The usual dosing for anxiety is 50-100 mg 4 times per day according to the FDA, but I would use caution with the dosing because in 2015 the European Medicines Agency announced a small but definite risk for QT interval prolongation and torsade de pointes in persons using hydroxyzine. It’s best to keep adult doses at 100 mg/day or less and 2 mg/kg/day in children weighing up to 40 kg. 
  • If possible, avoid hydroxyzine in the elderly or limit the dose to 50 mg/day 
  • For dosing be sure to use hydroxyzine in the lowest effective dose, avoid it in patients with known risk factors for cardiac arrhythmias or on medications that can increase the risk of QT prolongation. 
  • The anticholinergic activity of hydroxyzine is much lower than that of diphenhydramine, it’s more selective for the histamine receptors. There can still be some risk of cognitive impairment due to anticholinergic activity. 
  • Hydroxyzine is highly lipophilic and easily crosses the blood-brain-barrier. 
  • The half-life is around 24 hours 
  • Other common side effects include sedation, dry mouth, and tremor 
  • Hydroxyzine is contraindicated in early pregnancy and not recommended for breast feeding mothers. 
  • To sum things up, this medication offers an option for the short-term treatment of anxiety that is not addictive. It still has some risks and like most medications that target anxiety is not meant for long term management. 

Most Commonly prescribed Psychiatric Medications: Mirtazapine/Remeron

Mirtazapine is considered a noradrenergic and specific serotonergic antidepressant. It’s one of a newer generation of medications used to treat major depression. 

The mechanism is unique, and the noradrenergic effects are mediated by blockade of alpha-2 presynaptic receptors which results in an increase in norepinephrine. This is a negative feedback loop, which means norepinephrine in the synaptic cleft will bind to presynaptic alpha-2 receptors resulting in decreased norepinephrine release (hence the negative feedback). If we block the alpha-2 receptors preventing norepinephrine from binding it will allow more norepinephrine to be released. Essentially, we are taking the break off. 

Mirtazapine is also a histamine H1 receptor blocker which is the reason for many of the side effects including sleepiness and weight gain. 

The dose is usually 15 mg at bedtime and can be increased every 1-2 weeks to a maximum dose of 45 mg at bedtime. In some cases, doses of up to 90 mg at bedtime have been used. 

If the goal is sedation and help with sleep a 15 mg tab can be broken in half to 7.5 mg which is more sedating than 15 mg. Sedation associated with the affinity for H1 receptors and typically experienced at dosages of 15 mg/day may be counteracted by an increasing noradrenergic neurotransmission at dosages of 30 mg/day. The main point is higher doses result in less sedation because of increased noradrenergic effects. 

Be mindful of the propensity for weight gain with this medication. BMI and waits circumference should be monitored. 

The most common side effect of mirtazapine is sleepiness (54%), dry mouth (25%), increased appetite (17%), constipation (13%), weight gain (12%), weakness, dizziness, and flu like syndrome. 

This is a good choice for a depressed patient with difficulty sleeping, and poor appetite. It’s also a good choice for a patient who is concerned about sexual side effects. If a patient is concerned about weight gain and sleepiness this may not be the best medication for that person. It works well in combination with venlafaxine of desvenlafaxine. There is some evidence to support the use of mirtazapine in combination with haloperidol to treat the negative symptoms of schizophrenia. 

Aripiprazole (Abilify) Not Your Typical Dopamine Blocking Medication

Aripiprazole is a dopamine serotonin receptor partial agonist. Influencers like Joe Rogan have commented on this medication in past shows and there seems to be a lot of controversy surrounding its use in depression specifically. 

  • It’s approved for schizophrenia, acute mania/mixed mania, bipolar maintenance, depression (adjunct), autism related irritability, Tourette’s disorder, and acute agitation in schizophrenia or bipolar disorder in the IM form. 
  • This is a unique medication among dopamine blocking drugs, it acts as a partial agonist at dopamine D2 receptors. 
  • What does this mean? Theoretically it reduces dopamine output in states of excessive dopamine production such as schizophrenia mediating the positive symptoms (e.g. hallucinations) of the disorder.
  • Now how does it work to improve mood? Here it’s a similar concept, if dopamine levels are low, the partial agonism will increase dopamine output resulting in improved cognitive, negative, and mood symptoms 
  • There are several other receptor interactions associated with aripiprazole including D3 receptor activity, partial agonism at 5-HT1A receptors, blocks 5HT2A receptors which increases dopamine in some areas of the brain, blockade of 5HT2C and 5HT7 receptors which may contribute to the antidepressant effects. 
  • With Aripiprazole what you see is about a 60% dopamine blockade because of this partial agonist mechanism. Brexpiprazole (rexulti) has even less dopamine blockade about 20% overall do. This would theoretically worsen psychosis but would possibly help with depression.

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