Efficacy of pharmacological interventions in schizophrenia treatment Research

by Palak Parashar, Humaira Hasan, Upasana Koul

Introduction
Schizophrenia is a serious brain disorder affecting around 1% of the global population and is one of the top 10 causes of disability worldwide (Marder & Cannon, 2019). This condition is characterized by symptoms such as hallucinations (e.g., seeing or hearing things that aren’t there), delusions (false beliefs), disorganized speech, and abnormal behavior. Additionally, individuals with schizophrenia often experience a lack of motivation, reduced emotional expression, and cognitive difficulties, including problems with thinking, memory, and decision-making (Jauhar, Johnstone, & McKenna, 2022). The impact on daily life can be significant, leading to severe disability and incomplete recovery. Even individuals who show improvement may still struggle with social isolation, stigma, and limited opportunities for building close relationships. Unemployment rates are high among those with schizophrenia, and lifestyle factors such as poor diet, weight gain, smoking, and substance use contribute to a reduced life expectancy of 13 to 15 years (Hjorthøj, Stürup, McGrath, & Nordentoft, 2017; Kahn, 2020). The lifetime risk of death by suicide for individuals with schizophrenia ranges from 5% to 10% (McCutcheon, Reis Marques, & Howes, 2020).

Current diagnosis and treatment primarily target psychotic symptoms, but negative and cognitive symptoms are equally important due to their significant impact on social and professional functioning. These symptoms often do not respond well to conventional antipsychotic medications (Kahn, 2020; Jauhar, Johnstone, & McKenna, 2022). Historically, schizophrenia was conceptualized by Emil Kraepelin as “dementia praecox,” a term later renamed “schizophrenia” by Eugen Bleuler. Notably, both Kraepelin and Bleuler did not consider positive symptoms like delusions and hallucinations as the primary characteristics of the disorder. This historical perspective supports the view that a more comprehensive approach is needed for understanding and treating schizophrenia (Kahn, 2020).

Schizophrenia diagnosis involves a detailed psychiatric history and mental status examination, ruling out other potential medical and psychiatric causes of psychosis. Risk factors for developing schizophrenia include birth complications, being born in a specific season, maternal malnutrition, maternal influenza during pregnancy, a family history of the disorder, childhood trauma, social isolation, cannabis use, minority ethnicity, and living in urban environments (Messias, Chen, & Eaton, 2007; Davis et al., 2016). The exact cause and biological mechanisms of schizophrenia remain unclear due to its complexity and variability. Despite being relatively uncommon, schizophrenia has a significant impact on the global burden of disease, with more than half of those diagnosed experiencing multiple coexisting psychiatric and medical conditions (Chong et al., 2016).

The pharmacological treatment for schizophrenia:-

Pharmacological treatment for schizophrenia primarily involves antipsychotic medications, which are categorized into two groups:-

1.First-generation antipsychotics (FGAs)

2.Second-generation antipsychotics (SGAs)

1)First-generation antipsychotics, also known as typical antipsychotics, are dopamine receptor antagonists (DRA). These include:

Phenothiazines, trifluoperazine, perphenazine, prochlorperazine, acetophenazine, triflupromazine, mesoridazine

Butyrophenones: haloperidol

Thioxanthenes: thiothixene, chlorprothixene

Dibenzoazepines: loxapine

Dihydroindoles: molindone

Diphenylbutylpiperidines: pimozide. (Drummond N, McCleary L, Freiheit E, Molnar F, Dalziel W, Cohen C, Turner D, Miyagishima R, Silvius J. 2018 Jennings AA, Guerin N, Foley T. Faden J, Citrome L. Pharmacother. 2019) .

2. Second-generation antipsychotics, also known as atypical antipsychotics, are serotonindopamine antagonists. As of 2016, the Food and Drug Administration (FDA) has approved 12 atypical antipsychotics. These are:

Risperidone

Quetiapine

Aripiprazole

Asenapine

Lurasidone

Iloperidone

Brexpiprazole

Clozapine ( Haddad PM, Correll CU. Nov 2018) .

What is Schizophrenia?

Schizophrenia may be defined as an acute mental illness that is characterized by disturbance in cognition( illogical thinking), behavior, speech, and hallucinations(hearing voices, seeing things that aren’t present) or delusions. (American Psychological Association, n.d.)

The DSM-5, or the Diagnostic and Statistical Manual of Mental Disorders, describes the symptoms of schizophrenia as including disorganized speech (e.g., frequent derailment or incoherence), delusions, hallucinations, or catatonic behavior. (NCBI, n.d., Table 22)

Prevalence and Onset:

Schizophrenia is a genetic neurocognitive disorder that affects approximately 1% of the population, typically appearing between the ages of 21 and 25 in males and 25 and 30 in females. (Zhan et al., 2023) Extensive research suggests that from 1990 to 2019, global schizophrenia cases rose by over 65%, new diagnoses by 37%, and health impacts (DALYs) by 65%, while age-adjusted rates stayed stable. (Solmi et al., 2023)

Treatment:

Schizophrenia treatment is lifelong and combines medications with psychosocial support, guided by a psychiatrist and a care team. Antipsychotic medications, including both first- and second-generation options, are the primary treatment, with long-acting injectables available for better adherence. Additional medications, such as antidepressants or mood stabilizers, may be used based on individual needs. Psychosocial approaches like therapy, social skills training, family support, and vocational rehabilitation enhance coping, communication, and daily life skills. Severe cases may require hospitalization for stabilization, while electroconvulsive therapy (ECT) is considered for those unresponsive to other treatments. With proper care, many people with schizophrenia can manage their symptoms effectively. (Mayo Clinic, n.d.)

Prescribed Drugs

First-Generation Antipsychotics

First-generation antipsychotics (FGAs), also known as typical antipsychotics, primarily work by blocking dopamine receptors to alleviate symptoms of various mental health conditions. These medications are commonly prescribed for issues such as acute mania, agitation, and bipolar disorder. Some examples of FGAs include Chlorpromazine (Thorazine), Fluphenazine (Prolixin), Haloperidol (Haldol), and Loxapine (Loxitane), among others. (Mayo Clinic, n.d.)

Mechanism: Both first- and second-generation antipsychotics block dopamine in the ventral tegmentum to reduce positive symptoms. However, first-generation drugs also affect the nigrostriatal dopamine system, leading to extrapyramidal side effects, which second-generation drugs cause less frequently. (Grace & Uliana, 2023)

Efficacy:

Studies revealed minimal differences in efficacy between First Generation Antipsychotics and Second Generation Antipsychotics, but haloperidol was less effective than amisulpride and clozapine. Additionally, olanzapine showed greater improvement in functional capacity compared to quetiapine and ziprasidone. (Pike et al., 2009)

Second Generation Antipsychotics

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are newer medications that work differently from first-generation antipsychotics. Instead of fully blocking dopamine receptors, SGAs partially block them and may also influence other neurotransmitters like serotonin. Examples of SGAs include Aripiprazole (Abilify), Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone (Risperdal), and Quetiapine (Seroquel). (Mayo Clinic, n.d.)

Mechanism:

These medications inhibit some serotonin and dopamine receptors and stimulate other serotonin and dopamine receptors. (Cleveland Clinic, 2024)

Efficacy:

Patients with schizophrenia who were treated with SGAs showed significantly greater improvement in self-reported quality of life compared to those on FGAs, particularly when treatment was individualized. (Gründer et al., 2016)

Side Effects:

Studies show that olanzapine and risperidone are associated with the greatest weight gain, with olanzapine causing the largest increase in BMI. Paliperidone leads to the highest rise in total cholesterol but is the only drug to increase HDL cholesterol. Quetiapine XR shows the greatest reduction in fasting glucose, while lurasidone has the lowest weight gain, a reduction in BMI, and is the only treatment that decreases total cholesterol and triglycerides. Additionally, quetiapine XR is linked to the highest increase in both systolic and diastolic blood pressure. (Gründer et al., 2016b)

Clozapine

Clozapine is an FDA-approved atypical antipsychotic used for treatment-resistant schizophrenia. It is more effective than other antipsychotics for managing treatment-resistant schizophrenia and schizoaffective disorder. However, it is not the first-line treatment due to its potential for various adverse effects. (Haidary & Padhy, 2023) (Gammon et al., 2021)

Mechanism:

Clozapine acts as an antagonist by inhibiting dopamine D2 receptors and interacts with various serotonin receptors, such as 5-HT1A, 5-HT2A-C, 5-HT6, and 5-HT7. [13] Clozapine can also elevate norepinephrine levels, potentially alleviating depression and reducing suicidal tendencies in individuals with schizophrenia.(Khokhar et al., 2018)

Efficacy:

Research consistently demonstrates clozapine’s effectiveness in reducing positive symptoms in acutely psychotic and treatment-resistant patients, preventing the worsening of positive symptoms during maintenance therapy, and decreasing hostility and violent behaviors. Additionally, evidence indicates that clozapine may enhance social and occupational functioning as well as overall quality of life. (Buchanan, 1995)

Effectiveness when combined with CBT or other forms of therapies.

Schizophrenia is a severe mental disorder that can significantly impact a person’s ability to function, leading to disability and placing a major burden on society (GBD 2015 DALYs and HALE Collaborators, 2016). Effective treatment involves both pharmacological and psychological interventions. The National Institute for Health and Care Excellence (NICE) in the UK and the Schizophrenia Patient Outcomes Research Team (PORT) in the USA emphasize the importance of these approaches for managing the condition (National Collaborating Centre for Mental Health, 2009; Buchanan et al., 2010).

Recent research, including the Lancet Psychiatry Commission, has stressed the importance of improving psychological treatments for future advancements (Holmes et al., 2018).

Cognitive Behavioral Therapy (CBT) is the most extensively studied psychotherapy for schizophrenia. It is recommended in treatment guidelines (National Collaborating Centre for Mental Health, 2009). A systematic review and network meta-analysis of 53 studies revealed that CBT effectively reduces symptoms of schizophrenia, particularly positive symptoms, when compared to usual care and supportive therapies (Bighelli et al., 2018).

Effect sizes from these analyses showed:

Overall symptoms: −0.38 (95% CI −0.56 to −0.20)

Positive symptoms: −0.30 (95% CI −0.30 to −0.14)

Negative symptoms: −0.16 (95% CI −0.29 to −0.03)

However, the studies rarely report the number of patients who show significant improvement, and the criteria for improvement differ among studies. This inconsistency means that pairwise metaanalyses of CBT do not usually provide data on the rate of patient response. One exception is a Cochrane review by Jones et al., which combined response rates under the term “reliable change,” noting variations in definitions (Jones et al., 2012).

To better understand patient responses, Zhu and colleagues applied a method using continuous outcome data to calculate response rates from studies on antipsychotic medications for patients experiencing first-episode schizophrenia (Zhu et al., 2017).

Relapse and Side Effects in Schizophrenia Treatment

Pharmacological interventions, particularly antipsychotics, are essential in managing schizophrenia and preventing relapse. Second-generation antipsychotics (SGAs) like olanzapine and risperidone have been shown to significantly reduce relapse rates, outperforming first-generation antipsychotics (FGAs). However, these advantages are obtained at the cost of metabolic side effects such as weight gain, dyslipidemia, and diabetes frequently confronting long-term compliance with treatment (Leucht et al., 2020). Novel research highlights the fact that the continuation of medication alongside psychoeducation has resulted in decreased relapse by nearly 50%, thus improving patient prognosis (Catalan et al., 2021).

Although they are effective, side effects like sedation, extrapyramidal symptoms, and cognitive dulling remain; therefore, personalized management strategies are required. A 2022 meta-analysis indicated that adjustments in dose and additional therapies could counteract side effects and improve adherence and overall effectiveness (Lambert et al., 2022). Moreover, advancements in long-acting injectable antipsychotics offered more treatment alternatives for patients with difficulties in maintaining adherence to daily therapy (Voineskos et al., 2020). Overall, pharmacological interventions hold an important role in preventing relapse; however, preventing side effects needs complementation of such treatments.

Conclusion: The Combination of Pharmacological and Psychosocial Therapies

Schizophrenia is an illness with wide-ranging needs that should be addressed through polymodal treatment. Medications as antipsychotics are basic treatments but have the power to manage symptoms and develop a low risk of potential relapse. However, for treatment-resistant patients, clozapine has proven to be an effective medication, especially alongside psychosocial interventions such as CBT (Catalan et al., 2021). Indeed, such integrative treatments have shown to produce better outcomes as they not only address the biological components but also help shape the psychosocial aspects of schizophrenia (Voineskos et al., 2020).

For example, CBT serves as a supportive adjunctive treatment that addresses distorted thought, thereby enhancing functional recovery outcomes, whereas family-focused interventions decrease caregiver burden and enhance adherence (Lambert et al., 2022). Relapse has been reported in 2023 to be significantly reduced, with improvement in the quality of life metrics, by combining antipsychotics with CBT (Arya et al., 2023). In conclusion, although pharmacological interventions are the cornerstones in the treatment of schizophrenia, their amalgamation with other evidence-based psychosocial therapies is the comprehensive solution, resulting in improved long-term outcomes and patient well-being.

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