In my practice, I encounter many cases of first-episode psychosis, a critical period that requires thoughtful and precise intervention. The decisions made during this time can set a patient on the path to long-term recovery or, unfortunately, towards a lifetime of challenges.
There are a few guiding principles I always adhere to:
Most antipsychotics can be effective, but it’s important to choose carefully.
Lower doses often suffice to achieve remission in first-episode psychosis. Starting with a medication that has a lower risk of cardiometabolic side effects and weight gain is crucial, especially for young patients. They shouldn’t be burdened with long-term physical side effects as they navigate their recovery.
Predicting whether a patient will experience a single episode or develop a chronic condition like schizophrenia is challenging. While family history and substance use, particularly cannabis, can provide clues, there is still uncertainty.
I believe that after 6-12 months of treatment, it’s worth considering tapering the antipsychotic to the lowest effective dose, with a careful eye on any signs of relapse. Unfortunately, what I often see is that both patients and clinicians overlook the subtle signs of relapse because they’ve mutually decided to discontinue the medication. By the time I see them again, the situation has worsened.
Early psychosis treatment requires a delicate balance between managing symptoms and minimizing long-term side effects, all while keeping a close watch for signs of relapse. Careful planning is key to setting patients on the best path forward.
Schizophrenia is a complex and debilitating mental disorder characterized by a range of symptoms, including hallucinations, delusions, cognitive deficits, and emotional dysregulation. Despite advancements in antipsychotic medications, many patients experience incomplete symptom relief and significant side effects. As a result, there is a growing interest in alternative therapeutic targets, including the muscarinic acetylcholine receptors (mAChRs).
Muscarinic Acetylcholine Receptors (mAChRs)
The mAChRs are G protein-coupled receptors involved in various central nervous system functions, including cognition, learning, memory, and mood regulation. There are five subtypes of mAChRs (M1-M5), with the M1, M2, M3, and M4 subtypes playing significant roles in modulating neural activity related to schizophrenia.
M1 Muscarinic Agonists
The M1 receptor is primarily expressed in the cortex and hippocampus, regions crucial for cognitive processing. M1 agonists have shown promise in improving cognitive deficits and reducing psychotic symptoms in schizophrenia. Research indicates that M1 activation can enhance cholinergic neurotransmission and modulate glutamate and dopamine systems, potentially alleviating both positive and negative symptoms.
M2 Muscarinic Agonists
M2 receptors are predominantly found in the basal forebrain and play a role in modulating acetylcholine release. Although less studied than M1, M2 agonists may help balance neurotransmitter release, contributing to improved cognitive function and reduced psychotic symptoms.
M3 Muscarinic Agonists
The role of M3 receptors in schizophrenia is not as well understood as M1 and M4 receptors. However, M3 receptors are involved in various physiological processes, including insulin secretion and smooth muscle contraction. Research is ongoing to determine their potential therapeutic benefits in schizophrenia.
M4 Muscarinic Agonists
M4 receptors are highly expressed in the striatum, a brain region implicated in the regulation of motor control and reward processing. M4 agonists have shown potential in reducing dopaminergic hyperactivity, which is associated with positive symptoms of schizophrenia, such as hallucinations and delusions. Additionally, M4 activation may help mitigate side effects associated with conventional antipsychotics, such as extrapyramidal symptoms.
Clinical Implications and Future Directions
The therapeutic potential of M1-M4 muscarinic agonists in schizophrenia is an exciting area of research. Targeting these receptors may offer a novel approach to address the cognitive and negative symptoms of schizophrenia, which are often resistant to current treatments. Ongoing clinical trials and preclinical studies are crucial to understanding the efficacy, safety, and mechanisms of action of these compounds.
Conclusion The exploration of M1-M4 muscarinic agonists represents a promising frontier in the treatment of schizophrenia. By modulating cholinergic, glutamatergic, and dopaminergic systems, these agents have the potential to provide more comprehensive symptom relief with fewer side effects compared to traditional antipsychotics. Continued research and development are essential to bring these innovative treatments to clinical practice, offering hope for improved outcomes for individuals with schizophrenia.
Happy Friday Everyone, todays post is a topic near and dear to my heart
Clozapine is the most effective medication available for treating schizophrenia. In my work in community mental health, many of my patients could greatly benefit from clozapine, but significant barriers make access difficult. A large portion of my patients are homeless and frequently lost to follow-up, which complicates the already burdensome REMS (Risk Evaluation and Mitigation Strategy) program. To ensure access to this life-saving treatment, adjustments to the REMS program are necessary. One solution could be eliminating the requirement to report completed monitoring and post results on a central database. Additionally, restrictions that delay pharmacies from distributing clozapine should be removed. Finally, we need to reevaluate the frequent and, quite frankly, excessive monitoring of absolute neutrophil counts (ANC). These changes could significantly improve access for patients who need this critical medication.
I recently had an interesting discussion with one of our residents about the risk of developing schizophrenia after experiencing substance-induced psychosis. The conversation was sparked by a study based on data from the Danish Civil Registration System. Fun fact: when you see large data sets like this, they’re often from Scandinavian countries.
The study followed 6,788 people who were diagnosed with substance-induced psychosis between 1994 and 2014. They tracked patients until they developed schizophrenia, bipolar disorder, or passed away, using statistical methods to calculate the risk of conversion to a serious mental illness.
A key takeaway: this study didn’t just look at the risk of schizophrenia but also included bipolar disorder and various substances—not just cannabis. Overall, 32.2% of people with substance-induced psychosis went on to develop either schizophrenia or bipolar disorder. Cannabis-induced psychosis had the highest conversion rate, with 47.4% of those cases developing one of these disorders.
Being young and male increased the likelihood of developing schizophrenia, and self-harm after substance-induced psychosis was also linked to a higher risk of both schizophrenia and bipolar disorder.
The big takeaway here? Substance-induced psychosis is closely associated with the development of serious mental illnesses. Follow-up care is essential, and steering clear of cannabis is always a smart move.
As an inpatient psychiatrist, you encounter a wide array of stories and experiences. Many of my trainees find this to be the most fascinating and engaging part of the job. We have the unique opportunity to delve into the inner workings of the mind and understand the thought processes of patients with serious mental illnesses (SMI). One of the things that often emerges during our evaluations is the presence of various types of delusions. Some are more common than others, with persecutory and grandiose delusions being frequent examples. I often hear patients claim that unknown groups are conspiring to ruin their lives, or a manic patient might declare, “I’m Jesus Christ.”
Over the years, I’ve noticed that these delusions tend to remain consistent, with similar themes recurring during subsequent admissions. In case you’re wondering, I often see the same individuals with the same issues multiple times a year, giving me a wealth of data points to support this observation. This insight is supported by a recent article from JAMA Psychiatry, which found that delusional content remains consistent across episodes of psychosis. This consistency can help us recognize the early stages of decompensation and potentially intervene before hospitalization becomes necessary. For instance, if a patient claims, “I’m Jesus Christ” during one episode, it’s likely they will express the same delusion during future episodes.
Another significant finding from this study is the importance of maintaining the intensity of interventions throughout the follow-up period. Unfortunately, there are many reasons why this doesn’t always happen, but when it doesn’t, poor outcomes are often the result.
It wasn’t that long ago when I was sitting in lectures as a first-year psychiatry resident. I learned about the first- and second-generation antipsychotic medications in detail. One commandment that was always preached in my training was to never combine two antipsychotic medications because there is no additional benefit. Today we are here to explore this idea and see if there is truly no additional benefit to using two antipsychotics and explore why there is so much antipsychotic polypharmacy in serious mental illness.
Since most guidelines discourage the use of multiple antipsychotic medications, why are many psychiatrists going against these guidelines? In most cases we are just trying to stabilize patients, get them better, and keep them out of the hospital as the goal is to provide most psychiatric care in the community. To reach these goals a single medication does not always produce the desired results.
Patients that end up on multiple antipsychotics have some unique characteristics. They tend to have more severe psychotic symptoms, are male, unemployed, and younger. Those with frequent inpatient admissions on involuntary status are also more likely to end up on two medications.
What To Do When a Single Medication Is Not Enough?
The use of multiple antipsychotics is an area of limitted research. However, there is a difference between rational polypharmacy and irrational polypharmacy.
We should start this discussion by saying a patient should be started on monotherapy titrated to an effective dose and continued on the medication for 6 weeks prior to making a change. If the first medications fails, then switching to another medication or long acting injectable is a reasonable next step. If after another 6 weeks of treatment the patient remains unstable and symptomatic the technical next step is to start clozapine. There are many reasons why clozapine may not be a good option for a particular patient including the strict requirements for weekly complete blood cell counts CBCs.
Assuming this process is followed and the patient is still symptomatic what’s the next step?
Consider Receptor Binding Profiles
This is the first step in prescribing two medications rationally. Most first-generation medications such as Haldol will bind tightly to D2 receptors and stay bound to the sites longer. Second-generation medications like quetiapine are known to bind to the receptors and quickly dissociate giving an on-off like effect. Tight binding and longer duration of binding can lead to extrapyramidal side effects (EPS), whereas quick on-off medications like quetiapine have limitted EPS risk.
You should also consider other receptors the medication may target such as histamine and muscarinic cholinergic receptors. It would be best to avoid combining two medications that have high antihistamine and anticholinergic activity.
Let’s look at some scenarios where antipsychotic polypharmacy makes sense.
Patients With Acute Agitation
This is a common problem on the inpatient unit. A patient is on a low-potency quick on-off medication like quetiapine but remains symptomatic and is engaging in dangerous behavior.
The addition of a higher potency, higher affinity medication like Haldol makes some sense here. This will control the acute agitation, can be titrated until the psychotic aggression is controlled, and can be stopped as soon as the patient is stable on quetiapine. We can see how the receptor binding profile makes this combination reasonable.
Clozapine Refractory Patients
What do you do when a patient is on the best antipsychotic medication but remains symptomatic?
We do have several lines of evidence that we can look at for this question. One option is to add low dose risperidone. This is a similar idea to adding Haldol to quetiapine. Clozapine has lower affinity for the D2 receptor than risperidone which has much higher affinity for D2 receptors. There were two placebo-controlled trials that support this combination. Before combining medications, I would suggest obtaining a clozapine level to make sure it’s therapeutic.
There are two more recent studies that compared multiple antipsychotic medication combinations and used rehospitalization as a measure of effectiveness. Both studies found a significant reduction in rehospitalization for patients receiving polypharmacy compared to those receiving monotherapy. The best outcome was achieved when clozapine was combined with aripiprazole.
Patient is On a Long Acting Injectable (LAI) but Remains Symptomatic at the Highest Dose
This is a common problem because the doses of LAIs are limitted. For example, the LAI aripiprazole (Aristida) is limitted to a maximum dose of 20 mg/day. The oral formulations of aripiprazole allow for a maximum dose of 30 mg/day. One strategy is to give the injection early. This will usually be done on week 3 for formulations that last 4 weeks. Another option is to add another medication with a different receptor binding profile such as the clozapine aripiprazole combination that was shown to reduce the risk of rehospitalization.
Treatment of Insomnia
The addition of low dose quetiapine to a medication like paliperidone is common in clinical practice. Once D2 receptor blockade has been maximized by reaching an effective dose of paliperidone, considering the addition of as need (PRN) quetiapine for its low potency and sedating properties is reasonable. The medication should be used PRN only and should be removed once the insomnia has resolved. Consider a sleep study if sleep apnea is possible and using other options such as short-term orexin antagonists, melatonin, and sedating antidepressant if appropriate.
Treatment of Antipsychotic Induced Side Effects
I know what you are going to say, adding a medication to treat a side effect of another medication doesn’t make sense. Let’s take an example to illustrate why this makes sense. If a patient is stable on risperidone and is discovered to have an elevated prolactin level you have an obligation to address it. The addition of low dose aripiprazole has been proven to reduce prolactin levels in these cases. Another possibility is using aripiprazole to reduce the metabolic burden of medications such as clozapine. There is much more limited data in this area and I would consider metformin a much better option to start with if antipsychotic induced weight gain is a problem.
In the process of Switching Medication the Patient Achieves Remission
This is another common clinical scenario. A patient didn’t respond to a medication, and you begin decreasing the dose of the first medication while titrating the new medicine. Then suddenly they are better. You don’t know why but they are better than they have ever been and now you are afraid to make any additional changes. Ideally you would finish the process and appropriately titrate the new medicine while discontinuing the ineffective medication. There is no good data to support inadequate dosing of two antipsychotics, and it’s best to continue your taper/titration and reevaluate after it’s complete.
Conclusion
There is still limited data to support the use of multiple antipsychotic medications although it is often seen in clinical practice. There are a few places where the addition of a second medication makes sense, and we can use receptor profiles to help us make rational decisions and avoid excess side effect burden.
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).
Efficacy
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
-Dizziness
-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.
Agranulocytosis
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.
Dosing
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.
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
