Schizophrenia Today

Schizophrenia

Schizophrenia is among the most intricate and demanding psychiatric conditions, characterized by a diverse array of symptoms including disorganized and unusual thinking, delusions, hallucinations, inappropriate emotional responses, and disrupted social functioning. Schizophrenia impacts about 24 million individuals globally, equivalent to 1 in 300 people (0.32%). Among adults, this prevalence increases to 1 in 222 people (0.45%). While less common than many other mental health disorders, schizophrenia typically emerges in late adolescence or early twenties, often manifesting earlier in men than women. This disorder is commonly linked with substantial distress and impairment across various aspects of life including personal, family,, educational and occupational domains. Although research has not identified a single cause of schizophrenia, it is believed to result from the interaction between genetic predispositions and a variety of environmental factors.

The pathophysiology of schizophrenia involves complex and multiple molecular and neural circuit changes. Neurotransmitter imbalances are key to understanding the pathophysiology of schizophrenia, with dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) all playing significant roles. Excessive dopamine activity in the mesolimbic pathway, which extends from the ventral tegmental area to the limbic regions, is believed to contribute to the positive symptoms of schizophrenia. Conversely, reduced dopamine levels in the mesocortical pathway, connecting to the ventral tegmental area to the cortex, may be responsible for negative symptoms and cognitive deficits. Moreover, the nigrostriatal pathway is associated with extrapyramidal motor side effects caused by D2 receptor blockers, while the tuberoinfundibular pathway is linked to the hyperprolactinemia observed with the use of these blockers. 

Treatment Overview:

To diagnose schizophrenia, a comprehensive evaluation is essential, including a detailed mental status examination, psychiatric diagnostic interview, physical and neurologic examinations, complete family and social history, and laboratory tests to rule out any general medical or substance-induced causes of psychosis. Both first-generation antipsychotics, also referred to as traditional and second-generation antipsychotics (atypical) are utilized in treating schizophrenia. While second-generation antipsychotics generally produce minimal or no extrapyramidal symptoms (EPS) compared to first-generation antipsychotics, they also have a lower likelihood of causing tardive dyskinesia and do not significantly affect serum prolactin levels. However despite the reduced risk of neurological effects, second-generation antipsychotics are associated with increased metabolic side effects such as weight gain, hyperlipidemia, and diabetes mellitus.

Stage 1a of the treatment algorithm targets patients experiencing their initial acute episode of schizophrenia. Among second-generation antipsychotics (SGAs), aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone demonstrate efficacy in first-episode patients, with lurasidone showing effectiveness in  adolescents with schizophrenia, although most were not treatment naive. Quetiapine, associated with significant weight gain, is not recommended by certain guidelines, thus highlighting aripiprazole, risperidone, and ziprasidone as preferable options for first episode patients (Stage 1a). Stage 1B is geared towards patients who were previously treated with an antipsychotic and therapy is being restarted because the patient stopped taking the medication If significant symptom improvement and good tolerability are observed during the initial antipsychotic trial and the patient wishes to continue with the same medication, it may be restarted. Should an alternative medication be necessary, one from stage 2 should be considered. 

Stage 2 pertains to those patients who did not achieve satisfactory clinical progress with the antipsychotic administered in stage 1A or 1B, or those who initially responded but experienced a recurrence of symptoms while on medication. In this stage, the recommendation is monotherapy with either a first-generation antipsychotic or a second-generation antipsychotic which was not previously used in stage 1 or 1B. Clozapine is generally not advised at this stage due to safety concerns and the requirement for monitoring white blood cell (WBC) levels. However, it should be considered for patients exhibiting suicidal tendencies due to its efficacy in reducing suicidal behavior. Clozapine may also be an option for those patients with a history of violence or concurrent substance abuse. If a patient experiences intolerable side effects with the antipsychotic prescribed in stage 1A, 1B, or stage 2 an alternative antipsychotic therapy for that particular stage should be selected.

While schizophrenia poses significant challenges within the realm of psychiatric disorders, there are a range of medications that have demonstrated efficacy in managing symptoms. Effective management of schizophrenia entails adherence to prescribed medications, regular healthcare appointments, prompt symptom recognition, avoidance of alcohol and recreational drugs, and seeking support from organizations. These actions are crucial for optimizing treatment outcomes and improving quality of life for individuals living with schizophrenia. 

References:

1. professional, C. C. medical. (n.d.-b). Schizophrenia: What it is, causes, symptoms & treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/4568-schizophrenia 

2. Hany, M. (2024, February 23). Schizophrenia. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK539864/ 

3. Crimson, M. L., Smith, T., & Buckley, P. F. (n.d.). Schizophrenia. Shibboleth authentication request. https://accesspharmacy-mhmedical-com.jerome.stjohns.edu/content.aspx?sectionid=224358695&bookid=2577&Resultclick=2#1182457413

Schizophrenia is a severe neurological condition wherein individuals perceive reality in an abnormal manner, struggling to discern between genuine and imagined sensory stimuli. This condition typically manifests through delusions, hallucinations, peculiar physical behavior and disarrayed thought processes and communication. Patients with schizophrenia frequently experience paranoid ideation or auditory hallucinations. Schizophrenia can severely disrupt an individual’s life, posing challenges in daily and routine activities. 

The term “schizophrenia” itself is derived from Greek roots, with ‘schizo’ meaning splitting and ‘phren’ meaning pertaining to the mind, and was coined by Eugene Bleuler in 1908.Traditionally, symptoms of schizophrenia have been categorized into two distinct types: positive and negative symptoms. Common examples of positive symptoms are the hallucinations, delusions and thought disorders patients with schizophrenia often experience. On the other hand, negative symptoms include but are not limited to anhedonia (the inability to feel pleasure), lack of motivation and poverty of speech. While the prevalence of schizophrenia differs around the world, in the United States, it is estimated that about 0.6 to 1.9% of adults are affected by this condition. Interestingly, men tend to be slightly more susceptible to development of schizophrenia when compared to women. Additionally, Afro-caribbeans and their descendants have also exhibited a higher incidence of this condition. 

Several studies have proposed that schizophrenia’s onset stems from irregularities in multiple neurotransmitters such as a heightened activity in dopaminergic, serotonergic, and alpha-adrenergic systems or reduced activity in other neurotransmitters such as glutaminergic and GABAergic pathways. It has also been found that genetics play a profound role in the development of schizophrenia, as there has been approximately a 46% concordance rate among monozygotic twins and a 40% risk of schizophrenia when both parents are affected. Generally, there are three primary hypotheses used to explain the pathophysiology of schizophrenia: 

1. A neurochemical imbalance in dopamine, serotonin, glutamate and GABA

2. A neurodevelopmental disorder whereby cerebral structural abnormalities, such as the absence of gliosis, which suggest prenatal changes and consequently lead to motor and cognitive impairments

3. Neuroanatomical alterations determined through PET and MRI scans. PET and MRI scans will often reveal reduced grey matter volume in both the temporal and parietal lobes. 

Initial, first-line treatment for schizophrenia typically involves prescription of an oral second-generation antipsychotic such as Aripiprazole, Risperidone, Quetiapine, Lurasidone, etc. On a case-to-case basis, benzodiazepines such as Diazepam, Clonazepam or Lorazepam may be further added to the second-generation antipsychotic to manage any behavioral disturbances and relieve non-acute anxiety. While second-generation antipsychotic are the class of choice for first-line treatment of schizophrenia, first-generation antipsychotics such as Haloperidol or Fluphenazine may be appropriate when patients are unable to or have contraindications to taking second-generation antipsychotics. Once the patient has been stabilized from an acute episode of schizophrenia, it is often recommended to transition to a depot (parenteral) preparation of SGAs such as Aripiprazole, Palpperidone or Risperidone. This is because the transition to a depot medication has shown to improve outcomes and reduce relapses in schizophrenic patients. In addition to pharmacological intervention, non-pharmacological interventions such as cognitive behavioral therapy (CBT) or art/drama therapies have also been beneficial in addressing any negative symptoms patients may experience and aids in relapse prevention. 

Currently, there is a new possible treatment called KarXT (xanomeline-trospium) for schizophrenia that is being analyzed in a phase III trial. If this medication is to get approved by the FDA, this would be the first truly new drug with a unique mechanism of action that is used for the treatment of schizophrenia. Xanomeline alone is a dual M1 and M4-specific muscarinic receptor agonist and does not antagonize Dopamine (D2) receptors, unlike other medications currently approved for schizophrenia. With the addition of trospium chloride to Xanomeline in KarXT, which is a peripherally restricted muscarinic antagonist, this drug may be able to mitigate xanomeline-related adverse effects linked to peripheral muscarinic receptors. The EMERGENT-2 trial was a randomized, double-blind, placebo-controlled study that tested the efficacy of KarXT in patients with diagnosed schizophrenia. Patients who were eligible to participate in this trial were 18-65 years of age, had an official diagnosis of schizophrenia and exhibited recent exacerbation of psychosis necessitating hospitalization. Patients were to also have a PANSS (positive and negative syndrome scale) of 80 or higher and a clinical global impression-severity score of 4 or higher. Those who were assigned to the intervention group were initially administered KarXT 50mg/20mg for the first two days, followed by 100mg/20mg twice daily for days 3-7 and flexible dosing based on tolerability starting from day 8. The primary endpoint in this trial was the reduction in the participant’s PANSS score from baseline to week 5. Between December 2020 and April 2022, 252 participants were enrolled into the trial, 126 of which were randomized into the treatment group and 126 into the placebo group. The baseline PANSS score for the KarXT group and the placebo group was 98.3 and 97.9 respectively. By week 5, the primary endpoint was analyzed and revealed that the KarXT group had a mean change of -21.2 points versus the placebo group which only showed a -11.6 point difference from baseline (p<0.0001). The most common adverse effects that were noted in the KarXT group were constipation, dyspepsia, headache, nausea, vomiting, hypertension and dizziness. In conclusion, the EMERGENT-2 trial demonstrated efficacy in alleviating both positive and negative symptoms while maintaining good tolerability in patients who suffer from schizophrenia. These findings suggest that KarXT has a potential to be introduced as a novel class of antipsychotic medications with a unique MOA. Further data, however, is yet to be collected from the ongoing EMERGENT-3, 4 and 5 trials. 

Resources: 

Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170. doi:10.1016/S0140-6736(23)02190-6

What is Schizophrenia? . SAMHSA. April 24, 2023. Accessed May 2, 2024. https://www.samhsa.gov/mental-health/schizophrenia. 

Hany M, Rehman B, Azhar Y, et al. Schizophrenia. [Updated 2023 Mar 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539864/

Schizophrenia

Schizophrenia affects around 24 million people worldwide, with a slight incline in prevalence with males. This neurological disease can be defined as “a serious mental illness that affects how a person thinks, feels, and behaves.” This is an extremely difficult disease for the patient, as well as the patient’s family and friends to deal with because of the way schizophrenia affects the individual’s mental state. According to the National Institute of Mental Health, “people with schizophrenia may seem like they have lost touch with reality, which can be distressing for them and for their family and friends. The symptoms of schizophrenia can make it difficult to participate in usual, everyday activities, but effective treatments are available.” 

Symptoms for schizophrenia are important because early detection would mean treatment could be initiated earlier, hopefully yielding results faster. Symptoms for schizophrenia can be put into one of three categories: psychotic symptoms, negative symptoms or cognitive symptoms. Psychotic symptoms affect the way in which the patient thinks and feels, sometimes making it seem like they are a completely different person. These symptoms can be any of the following: hallucinations, thought disorders, movement disorders and delusions. Hallucinations can include visual, auditory, or any of the other sensory hallucinations. Hearing voices is the most common symptom of schizophrenia and usually happens for a while before it is noticed by family or friends. The patient’s thoughts and movements will be very unusual and a little out of whack, making this symptom very noticeable. Delusions can include a patient being paranoid about doctors wanting to rob them or wholeheartedly believing they are a spy. Negative symptoms are all the negative things that are associated with this neurological disorder, meaning anything that shows that the patient is uninterested in things they once were, a loss of motivation, withdrawal from friends and family, or any difficulty with showing emotions or functioning normally. These symptoms can include: having trouble planning and attending activities, experiencing no pleasure in everyday life, speaking in a dull voice and having no facial expressions and showing no emotion, avoiding social interactions or having only awkward interactions and having extremely low energy. Cognitive symptoms would be difficult in areas like thinking, focusing and remembering things. These symptoms tend to affect the patient’s life the worst, due to the big impact it has on their independence. Because simple things such as remembering appointments and eating breakfast become dangerous, they now need another person to remind them to do these tasks. These symptoms can include: having difficulty making decisions and processing the information necessary to make these decisions, difficulty using information right after it is learned or taught to the individual and difficulty keeping focus or attention. 

There are many risk factors associated with schizophrenia that are categorized into genetics, environmental factors and brain structure or function. In terms of genetics, schizophrenia can sometimes run in a family, but this does not mean it is genetic. There have been many studies and while there are certain genes that were found that increase a person’s likelihood of developing the mental disorder, there is no proof that this disease is hereditary. The other genes that have been found can be tested for if an individual is suspected of having schizophrenia or has a family member who suffers from it. The environmental factor is a combination of the genetic factors and aspects of the individual’s environment along with their life experiences. These three things can play a critical role in a patient developing schizophrenia. The individual environmental factors include living in poverty, stressful or dangerous areas, and/or exposure to illnesses (like viruses) or nutritional problems before birth. The brain factors can be examined through medical x-rays. According to studies, “people with schizophrenia may be more likely to have differences in the size of certain brain areas and in connections between brain areas.” This proves to be a more definitive risk factor because this is something tangible and can actually be seen by doctors, medical professionals and the patient and/or their family. It is also stated that these defects could be present from before birth, meaning this was the way the brain was developed from within the womb. 

After correctly identifying risk factors and assessing symptoms, the diagnosis for schizophrenia is made, which means the next step will be choosing a medication regimen. Most treatments will be patient centered, meaning managing their symptoms and improving their quality of life are top priorities when choosing their medications. It is also essential to consider any life goals or personal goals that the patient may have and want to accomplish, such as an education path or fulfilling a personal relationship. Antipsychotics are the top choice for treating schizophrenia because they can ease symptoms and make them less intense and less frequent. There are an abundance of options into terms of what route of administration the patient would prefer, which can help eliminate the issue of nonadherence. There are pills that the patient can take daily, or there are antipsychotic injections that patients can have once or twice monthly, if taking pills is an issue or they tend to forget to take their meds. Like with any other medication, there is no guarantee that every medication will work for all patients. When taking antipsychotics, there will be a lot of trial and error, and if the antipsychotics prove to be ineffective, there is also the option of taking clozapine. The only difference with clozapine is that the patient must be getting blood tests regularly to check on their ANC (absolute neutrophil count) levels in order to prevent neutropenia, a very dangerous side effect associated with the use of clozapine. Side effects for the antipsychotic medications include: weight gain, dry mouth, restlessness, and drowsiness. It is important to inform the patient of these side effects so they know what to expect when they begin taking them. They should also be informed that most of them will subside after continuous use, but some will stay for as long as they’re on the medication. 

References:

“Schizophrenia.” National Institute of Mental Health, U.S. Department of Health and Human Services, www.nimh.nih.gov/health/topics/schizophrenia. Accessed 28 Aug. 2023. 

“What Is Schizophrenia?” What Is Schizophrenia?, https://www.psychiatry.org/patients-families/schizophrenia/what-is-schizophrenia. Accessed 28 Aug. 2023.

Written by Justin Ayob and Antonio Ortega

Schizophrenia is a chronic, severe, and disabling thought disorder that occurs in ~1% of all societies regardless of class, color, religion, or culture. The cause is multifactorial and includes altered brain structure and chemistry, primarily involving dopamine and glutamine. Genetics (inherited susceptibility) and environmental factors are important in disease development. Patients suffer from hallucinations (sensing something that is not present), delusions (false beliefs), and disorganized thinking/behavior. They can withdraw from the world around them and enter a world of psychosis, where they struggle to differentiate reality from altered perceptions. Schizophrenia ranges from relatively mild to severe. Some people can function adequately in daily life, while others need specialized, intensive care. Treatment adherence is important and often difficult to obtain, primarily due to the patient's inability to recognize their illness. Many patients with schizophrenia live a life of torment where they cannot care for themselves. This condition has one of the highest suicide rates.

Schizophrenia is a thought disorder involving abnormal neurotransmitters. Patients with schizophrenia have increased dopamine levels, and may also have changes in glutamate levels. Dopamine and glutamate modulate each other, but the role of glutamate in schizophrenia is not well understood. Genetics, environment, stressors and some drugs can also be contributing factors.

Below is a detailed chart overview of the treatment and management of Schizophrenia

References:

2021 RxPrep: Chapter 64 : Schizophreina/Psychosis. Pages 892-900.

Schizophrenia is a chronic disorder of the brain that affects less than one percent of the United States population. When a person a diagnosed with schizophrenia, some of the symptoms they experience are delusions, hallucinations, disorganized speech, trouble with thinking and lack of motivation. There is currently no cure for schizophrenia and there is always research being conducted to lead a safer and innovative advancement in treatment options. Experts are also learning more about the cause of the disease by studying genetics, conducting behavioral research, and using advanced imaging to examine the brain’s structure and function. These new approaches are more promising in leading us towards more efficacious treatments.

There is a ton of misinformation about schizophrenia that spreads throughout the public population. Some people believe it can mean having multiple personalities or split personalities, but that is not really the case. There is also an idea that people with schizophrenia are dangerous, which is also not true. They are jus as dangerous as the average person. It is also thought that, due to the lack of mental health resources in the community, it leads to schizophrenia patients being homeless or living in hospitals. However, most patients with schizophrenia live with their family, in group home, or on their own.

There is research that shows schizophrenia affects men and women fairly equally, but men may have an earlier onset of this condition compared to females. Patients with this condition also are more likely to die younger than the general population because of the high rates of co-occurring medical conditions such as heart disease and diabetes.

There are many different symptoms of schizophrenia can affect and individual’s daily life. Some symptoms that are present are hallucinations, such as hearing voices or seeing things that do not exist, paranoia, and exaggerated or distorted perceptions, beliefs, and behaviors. Patients will also experience a loss or decrease in the ability to initiate plans, speak, express emotions, or find pleasure. Another symptom is confused and disordered thinking and speech, trouble with logical thinking and sometimes bizarre behavior or abnormal movements. Schizophrenia also has an impact on cognition where patients have issues with attention, concentration and memory, and declining educational performance. These patients also are at a higher risk for drug abuse than the general population.

Although there is no cure, many patients have minimal symptoms and tend to do okay. There are many antipsychotic medications prescribed to treat schizophrenia and they tend to be more effective in reducing symptoms during the acute phase of the condition. These medications also help reduce future acute episodes and their severity. Some of the medications used are first generation or typical antipsychotics and second generation or atypical antipsychotics. Some of the first generation drugs would be chlorpromazine, fluphenazine, haloperidol, perphenazine, and more. Some of the second generation antipsychotics are aripiprazole, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, ziprasidone, and more. There are many side effects of taking antipsychotic medications as well such as weight gain, sexual problems, drowsiness, dizziness, restlessness, dry mouth, constipation, nausea, blurred vision, low blood pressure and seizures. They also have to have regular doctor visits when taking these medications. There are many difficulties living with schizophrenia and there should be more education surrounding this illness and mental health awareness overall.

References:

1. “What Is Schizophrenia?” What Is Schizophrenia?, https://www.psychiatry.org/patients-families/schizophrenia/what-is-schizophrenia.

2. “Medications Used to Treat Schizophrenia.” WebMD, WebMD, https://www.webmd.com/schizophrenia/medicines-to-treat-schizophrenia.