Clinical Pearls: Schizophrenia - An Overview
March 8, 2023
By Maria Ahmed
This article is part of a series appearing in
Interactions, our biweekly newsletter, written and researched by CSHP's students. We've created this series as a valuable learning activity for pharmacy students undertaking rotations at CSHP. Crafting these pieces not only helps students gain in-depth knowledge of specific conditions, treatments, and resources, it also helps them hone their skills in research, critical appraisal, evaluation, synthesis, and writing – all of which will serve them well in clinical practice. The Professional Practice Team works with the students to select hot topics that are of interest and utility to both the students and to you, the reader. We hope you enjoy this piece by one of our future colleagues! Let us know what you think: If you would like to provide any comments or constructive feedback for our students, please email us at email@example.com.
Schizophrenia is a mental disorder that affects an individual’s interaction and understanding of the world.1 It is characterized by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions.1 According to national data (2016-2017) of ages 10+, 147,500 Canadians used health services for schizophrenia, of which, 60% were men.2 The all-cause mortality rate in individuals who were diagnosed with schizophrenia was 2.8 times higher than those who are not.1,2 As with all mental disorders, schizophrenia is identified on the basis of clinical features. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) demonstrates a spectrum of symptomatic domains for psychosis and the manifestation of multiple diagnostic categories.3,4 Confirming a diagnosis can be difficult, but it is crucial to identify the most appropriate treatment modalities by taking a holistic approach.4 In terms of treatment, antipsychotic medications are highly effective for target symptoms, however, the prevention and management of adverse effects and drug interactions should be monitored carefully in an acute setting.5 In Canada, the adverse drug events (ADE) rate is 7.5 per 100 hospital admissions where 20.8% result in death.6 Pharmacists have been shown to improve treatment and economic outcomes and endorse a multidisciplinary care approach when administering antipsychotic medications and managing adverse events.5 Clinical pharmacists also assist with recommending dosage adjustments, assessing adherence, and administering standardized rating scales to monitor improvement.6 Before diving into treatment, it is important to understand the pathophysiology of schizophrenia and the symptoms that arise.6
Pathophysiology and Symptoms
Abnormalities and imbalances of neurotransmitters have provided the basic theories on the pathophysiology of schizophrenia.7 The neurotransmission theories incorporate either excess or deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Specifically, dopamine receptor sites (D2) are thought to be associated with the pathophysiology of schizophrenia.7 The four dopamine pathways are: (1) mesolimbic (2) mesocortical (3) nigrostriatal (4) tuberoinfundibular.7 These dopamine pathways help us understand the symptoms of schizophrenia and side effects caused by antipsychotic medications.5 There are two main heterogeneous characteristics of symptoms: positive and negative.7 Positive symptoms reflect an excess of normal function regulated by the mesolimbic dopamine pathway in the brain that can manifest in hallucinations, delusions, disorganized speech and behaviour, catatonic behaviour and thought disorder.7 Whereas negative symptoms reflect the absence of normal behaviours related to motivation and interest regulated by the mesocortical dopamine pathway in the brain.5 The current antipsychotic medications effectively manage positive symptoms, whereas, there are currently limited treatment options available for negative symptoms, indicating that there is an unmet medical need.7
Treatment Options in the acute setting
Establishing patient-centered care and developing an alliance with the patient and the family is essential to formulate treatment plans and allow the patient to connect with their community.8-10 If involuntary hospitalizations are required when the patient poses a serious threat of harm to self or others, selecting the appropriate medication is routinely guided by the side effect profile and efficacy within the medication classes.8-10 Antipsychotic medications are generally the main cornerstone of schizophrenia management and initiation of treatment is vital within five years of an acute episode, as it is when most illness-related changes occur in the brain.8-10 Table 1 displays the medication classes, their main characteristics, and the monitoring parameters of antipsychotic medications. In an acute event displaying positive symptoms, the main goal of treatment is to decrease hostility and to allow the patient to return to normal functioning within seven days and with appropriate dosing and titration based on the patient’s response.8 Treatment during the acute phase is generally followed by a 12-month maintenance therapy where the main goal of treatment is to increase socialization, improve self-care and prevent relapses.8 It is important to avoid relapses, as one study demonstrated that over a 7-year follow-up, 80% of patients with schizophrenia had a significant correlation between the degree of deterioration and the number of relapses the patients experienced.11 In order to prevent relapse and re-hospitalization, maintenance therapy is required.6,12 One study showed the incidence of relapse among patients receiving maintenance therapy compared to those who have not received maintenance therapy was 18-32% versus 60-80%, respectively.6,12
The majority of guidelines recommend second-generation antipsychotic medications (SGA) – with the exception of clozapine - over first-generation antipsychotic medications (FGA) when treating a first-episode schizophrenia patient due to the side effect profile.13-16 Clozapine is reserved for refractory psychosis due to the risk of agranulocytosis and its’ weak affinity to D2 receptors.13-17 If the initial acute treatment of antipsychotic is not effective or tolerated after an adequate trial of an appropriate dose antipsychotic, switching to a different monotherapy treatment is recommended. The ultimate choice of selecting an antipsychotic should consider patient factors and preferences, the risk of metabolic effects, the trajectory of response, and the patient’s symptom patterns.13-17 If there is no response to the optimized medication regimen after 2-4 weeks, a change of the medication can be considered by a cross-taper method (minimizes withdrawal-emergent effects) or a delayed withdrawal method (preferred when relapse is a concern).19 If there is a partial response, the response to treatment can be assessed after an adequate trial of ≥ 4-6 weeks at ≥50% of the dose and can typically require at least 20% of improvement in symptoms via the reduction in Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS), to name a few.13-17
There is advocacy to use long-acting injections earlier in course of treatment and should not only be considered for non-adherence concerns.19-21 In a 2015 RCT, Subotinik et al compared the clinical efficacy of the long-acting injection (LAI) and oral formulation of risperidone within the first episode of schizophrenia.21 The results demonstrated a statistically significant lower rate of psychotic exacerbation and/or relapse in the LAI of risperidone compared to oral formulation (RRR 84.7%).21 In a systematic review and analysis of mirror-image studies, Kishimoto et al demonstrated that LAIs showed a strong superiority compared to oral antipsychotic medications in preventing hospitalization.27 It is important to stay vigilant and counsel patients with LAI treatment, as LAI can induce extrapyramidal symptoms (EPS).22
Management of Extrapyramidal Symptoms
From dopamine-receptor blocking agents, extrapyramidal symptoms (EPS) are one of the most common adverse drug effects patients experience).28,29 They can manifest within 24-48 hours of treatment and if not treated appropriately, can have detrimental effects on the patient long term such as bone deformities or significant motor impairment, or potentially lead to death.28,29 A variety of movement phenotypes have been described along the EPS spectrum, including dystonia, akathisia and parkinsonism.28,29 Pharmacists play a key role in managing the adverse effects of EPS and handling polypharmacy within this patient demographic.30 Often when managing adverse effects, rather than changing the medication or the dose of the offending medication, physicians tend to add a new medication to counteract the adverse effect.30 It is important to note the drug-induced EPS and manage it appropriately by first targeting the offending agent itself.30
With a prevalence of approximately 20%, it can manifest in tremors (“pill-rolling” type), rigidity (cogwheel) or bradykinesia (mask-like expression, shuffling gait, slowness of movement) where 90% occur within the first 6 weeks of treatment and does not stop throughout the clinical course of the treatment. Other psychological symptoms include slow thinking, fatigue, and cognitive impairment where the most at-risk populations include elderly females, high potency of FGA, HIV infection, family history of Parkinson’s disease, those with pre-existing neurological damage (e.g. stroke), discontinuing anticholinergics, and adding a second antipsychotic. The treatment includes either decreasing the dose of the antipsychotic, changing the antipsychotic or supplementing with anticholinergics.
Acute Dystonia and Akathisia19
Acute dystonia is torsions and spasms of the muscle located around the head and neck whereas acute akathisia is motor restlessness, fidgeting, pacing, rocking, swinging and intense urge to move. Acute dystonia can occur within 24-48 hours after the first dose and 90% occur within the first week of treatment and 90% of acute akathisia episodes can occur within the first 6 weeks of treatment, mainly with higher doses. Both acute states include a high-risk patient demographic that has a high potency of FGA. If not treated, acute dystonia can result in acute laryngeal/pharyngeal dystonia that can be life-threatening and acute akathisia can increase risk of tardive dyskinesia and can contribute to suicide and violence. One main difference in treatment is that acute dystonia can be treated by antiparkinsonian drugs, whereas in acute akathisia, antiparkinsonian drugs are not very effective. Both can also be treated by reducing the dose, changing the antipsychotic or adding lorazepam.
Tardive Dyskinesia vs Dystonia vs Akathisia19
Tardive dyskinesia is the involuntary movements that are abnormal to the face (ticks, frowning), lips (pursing, smacking), jaw (chewing, clenching), tongue (rolling), eyelids (blinking), limbs (tapping), trunk (rocking), and neck (nodding). The onset is after 3 or more months of therapy. These symptoms can disappear during sleep and the most at-risk populations include those aged over 40, female, history of EPS, chronic use of FGA, cognitive impairment, alcohol or drug abuse or organic brain damage. Whereas tardive dystonia is the sustained muscle contractions the of face, jaw, tongue, eyes, neck, links, back or trunk. It can occur after months/years of therapy in high-risk populations, which include young males, coexisting tardive dyskinesia, akathisia or mental retardation. Treatment options include switching to a different SGA or third-generation antipsychotic (TGA) or adding an anticholinergic. Tardive akathisia treatments also include adding beta-blockers such as propranolol. However, discontinuing the antipsychotic early can increase the chance of remission in all three states.
Table 1: Characteristics of first, second, and third generation of antipsychotic medications to treat schizophrenia23
It is important to note that schizophrenia can lead to negative health outcomes and early death as well as economic loss at a national and global scale.24-26 Without proper medication management, the risk of drug therapy problems increases the risk of hospitalization, morbidity, mortality, and healthcare expenditure Patients with schizophrenia are often treated with several medications for severe diseases and this opens the risk of polypharmacy and irrational combinations of medications.24-26 Pharmacists provide a promising approach to improve medication adherence and establish a collaborative approach in primary care settings.24-26 A systematic review of the impact of clinical pharmacists’ interventions in patients demonstrated multiple positive outcomes of various services within the psychiatric setting24. A few positive outcomes included improved adherence to antipsychotic treatment guidelines, decreased drug-related problems, decreased drug-drug interactions, improvement in patient quality of life, and cost-saving interventions were implemented.24-26 A scoping review of a clinical pharmacist in a mental health hospital setting demonstrated that the incorporation of clinical pharmacists improves medication management by providing guidance, identifying gaps in complex health needs, establishing evidence-based studies, facilitating the transition of care through medication reconciliation and follow-up, and reducing overall hospital admissions.24 Pharmacists have shown they are vital to team-based collaboration for patient-centered care to successfully improve patient quality of life.24-26
- U.S. Department of Health and Human Services. (n.d.). Schizophrenia. National Institute of Mental Health. Retrieved November 3, 2022, from https://www.nimh.nih.gov/health/statistics/schizophrenia
- Canada, P. H. A. of. (2020, July 6). Government of Canada. Canada.ca. Retrieved November 3, 2022, from https://www.canada.ca/en/public-health/services/publications/diseases-conditions/schizophrenia-canada.html
- American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition. Arlington (VA): American Psychiatric Association; 2013.
- Abidi S, Mian I, Garcia-Ortega I, et al. Canadian Guidelines for the Pharmacological Treatment of Schizophrenia Spectrum and Other Psychotic Disorders in Children and Youth. The Canadian Journal of Psychiatry. 2017;62(9):635-647. doi:10.1177/0706743717720197
- Goldstone, L. W., DiPaula, B. A., Werremeyer, A., Botts, S., Hepburn, B., Liu, H. Y., Duckworth, K., Young, A. S., & Kelly, D. L. (2021). The role of board-certified psychiatric pharmacists in expanding access to care and improving patient outcomes. Psychiatric Service.2021;72(7):794–801. https://doi.org/10.1176/appi.ps.202000066
- Baker GR, Norton PG, Flintoft V, Blais R, Brown A, Cox J, Etchells E, Ghali WA, Hébert P, Majumdar SR, O'Beirne M, Palacios-Derflingher L, Reid RJ, Sheps S, Tamblyn R. The Canadian Adverse Events Study: the incidence of adverse events among hospital patients in Canada. CMAJ. 2004 May 25;170(11):1678-86. doi: 10.1503/cmaj.1040498. PMID: 15159366; PMCID: PMC408508.
- Correll CU, Schooler NR. Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment. Neuropsychiatr Dis Treat. 2020 Feb 21;16:519-534. doi: s10.2147/NDT.S225643. PMID: 32110026; PMCID: PMC7041437
- Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P T. 2014 Sep;39(9):638-45. PMID: 25210417; PMCID: PMC4159061.
- Lehman AF, Lieberman JA, Dixon LB, et al. American Psychiatric Association Practice Guidelines; Work Group on Schizophrenia. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. (2nd ed) 2004;161(suppl 2):1–56.
- Castle DJ, Buckley PF. Schizophrenia. Oxford, United Kingdom: Oxford University Press; 2008.
- Curson DA, Barnes TR, Bamber RW, Platt SD, Hirsch SR, Duffy JC. Long-term depot maintenance of chronic schizophrenic out-patients: the seven year follow-up of the Medical Research Council fluphenazine/placebo trial. III. Relapse postponement or relapse prevention? The implications for long-term outcome. Br J Psychiatry. 1985;146:474–480. doi: 10.1192/bjp.146.5.474.
- Leucht S, Barnes TR, Kissling W, et al. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized controlled trials. Am J Psychiatry. 2003;160(7):1209–1222.
- Correll, C.U., Martin, A., Patel, C. et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophr 8, 5 (2022). https://doi.org/10.1038/s41537-021-00192-x
- Galletly, C. et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust. N. Z. J. Psychiatry 50, 410–472 (2016).
- Texas Medication Algorithm Project (TMAP). Texas Medication Algorithm Project (TMAP) Procedural Manual. (2008). Available at: https://jpshealthnet.org/sites/default/files/inline-files/tmapalgorithmforschizophrenia.pdf.
- Mental Health Clinical Advisory Group, Oregon Health Authority. Mental Health Care Guide for Licensed Practitioners and Mental Health Professionals. (2019). Available at: https://sharedsystems.dhsoha.state.or.us/DHSForms/Served/le7548.pdf.
- Crismon L, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et al., editors. 1Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, New York: McGraw-Hill; 2014. pp. 1019–1046.
- Srifuengfung M, Sukakul T, Liangcheep C, Viravan N. Paliperidone palmitate-induced facial angioedema: A case report. World J Clin Cases. 2020;8(20):4876-4882. doi:10.12998/wjcc.v8.i20.4876
- Remington G, Addington D, Honer W, Ismail Z, Raedler T, Teehan M. Guidelines for the Pharmacotherapy of Schizophrenia in Adults. The Canadian Journal of Psychiatry. 2017;62(9):604-616. doi:10.1177/0706743717720448.
- Malla A, Tibbo P, Chue P, et al. Long-acting injectable antipsychotics: recommendations for clinicians. Can J Psychiatry. 2013;58(5 Suppl 1):30S-35S.
- Subotnik KL, Casaus LR, Ventura J, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015;72(8): 822-829.
- Kim DD, Lang DJ, Warburton DER, Barr AM, White RF, Honer WG, Procyshyn RM. Exercise and Worsening of Extrapyramidal Symptoms during Treatment with Long-Acting Injectable Antipsychotics. Pharmacy (Basel). 2021 Jul 3;9(3):123. doi: 10.3390/pharmacy9030123. PMID: 34287361; PMCID: PMC8293348.
- Procyshyn, R., Bezchlibnyk-Butler, K. Z., & Jeffries, J. J. (2021). Clinical Handbook of Psychotropic Drugs. Hogrefe Publishing.
- Javedh S, Padma R, Sridhar BS, Shariff A, et al. A Systematic Review on the Impact of Clinical Pharmacist Interventions in Patients with Mental Health Disorders.Clin Schizorph Relat Psychoses. 2020;14:3.
- Ambed Mishra, G Sai Krishna, A. Sravani, Tony D. Kurian, Justin Kurian, M. Ramesh, M. Kishor. Impact of pharmacist-led collaborative patient education on medication adherence and quality of life of schizophrenia patients in a tertiary care setting, Bulletin of Faculty of Pharmacy, Cairo University, 2017;55(2):345-349.
- Mechaiel Farag, Leanne Chalmers, Kreshnik Hoti, Jeff Hughes. The role of the clinical pharmacist in mental health hospital-in-the-home: A scoping review. Research in Social and Administrative Pharmacy. 2022;18(10):3724-3735.
- Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry. 2013 Oct;74(10):957-65. doi: 10.4088/JCP.13r08440. PMID: 24229745.
- Tamara Pringsheim, MD MSc, Asif Doja, MD MEd, Stacey Belanger, MD PhD, Scott Patten, MD PhD, The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guideline group, Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth, Paediatrics & Child Health, Volume 16, Issue 9, November 2011, Pages 590–598, https://doi.org/10.1093/pch/16.9.590
- D'Souza RS, Hooten WM. Extrapyramidal Symptoms. [Updated 2022 Aug 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534115/
- Hashimoto Y, Tensho M. Effect of pharmacist intervention on physician prescribing in patients with chronic schizophrenia: a descriptive pre/post study. BMC Health Serv Res. 2016 Apr 26;16:150. doi: 10.1186/s12913-016-1408-4. PMID: 27117589; PMCID: PMC4847190.