Navigating Schizophrenia Treatment: Balancing Symptom Relief and Long-Term Needs

Abstract

Schizophrenia is a long-term disease that needs to account for acute symptom control and long-term treatment needs such as relapse prevention, remission, and safety. The aim of the present book chapter was to summarize available literature data and guidelines on how to treat specific symptoms of schizophrenia and what aspects to consider long term. Looking at single symptoms, clozapine was better than all other antipsychotics in addressing positive and hostility symptoms of schizophrenia: however, it is not first-line treatment. Cariprazine showed superior efficacy in treating primary negative symptoms and is treatment of choice for these symptoms. Additionally, partial agonists (aripiprazole, brexpiprazole, cariprazine) were better in addressing comorbid substance use, while quetiapine, cariprazine, and olanzapine/fluoxetine showed advantages in treating mood disorders. In long term, there was no difference between antipsychotics in addressing relapse and remission; however, distinct differences in safety aspects are seen; overall, newer generation antipsychotics (aripiprazole, brexpiprazole, cariprazine, and lurasidone) are favored over other antipsychotics. In summary, careful consideration should be applied when choosing the right treatment for schizophrenia, accounting for prevalent symptoms, longitudinal aspects, psychiatric and somatic comorbidities as well as preference of patients.

1. Introduction

Schizophrenia, a complex mental disorder, historically condemned patients to perpetual institutionalization. The absence of targeted therapies resulted in prolonged stays within psychiatric facilities and devoid of hope for reintegration into society [1]. The advent of antipsychotic medications (AP) revolutionized psychiatric care, aiming to alleviate positive symptoms and allow for a more humane life for patients. Despite their adverse effects, they offered a glimmer of hope for patients who had long been locked away; hence, these side effects were tolerated. Subsequent generations of antipsychotics expanded their scope, addressing additional unmet needs beyond positive symptom control [2].

While all medicines of the antipsychotic class can address symptoms of psychosis, AKA positive symptoms [3], they vary in the way they can address other symptoms of schizophrenia, including negative [4], cognitive [5], mood symptoms [6], hostility and anxiety, but also comorbidities with substance use [7] or mood disorders. Additionally, considerations extend to relapse prevention, remission, and overall functional outcomes. As a result, psychopharmacological treatment today is rather focused on remission and reintegration than just purely symptom control [8]. So, to choose an effective holistic treatment for schizophrenia patients addressing their symptoms along with accounting for longitudinal outcomes must be considered.

A symptom-based approach considers the various symptoms of schizophrenia and identifies the most suitable treatment for each specific symptom. It is a case-by-case approach always addressing the prominent symptom first. This is especially needed in acute patient care where severe positive symptoms, hostility, or self-harm need to be addressed immediately [9]. The longitudinal approach recognizes schizophrenia as a chronic condition, necessitating long-term management [10]. While addressing the prevailing symptom is essential, it is not the sole focus. Instead, treatment aims for sustained stability, functional improvement, and quality of life. Factors, such as relapse prevention, maintaining remission, and promoting recovery, become paramount [8]. The patient-centered approach combines both approaches and hence ensures holistic care for individuals navigating the complexities of schizophrenia. Clinicians collaborate with patients to find the most suitable treatment regimen over the long haul, balancing symptom control with minimizing side effects and optimizing functioning [11].

This review aims at examining symptom-based treatment strategies and summarizing available evidence, along with longitudinal treatment aspects, which consider safety and long-term functioning/quality of life of patients.

2. Symptom-based treatment strategies

Generally, three major symptom clusters are distinguished in schizophrenia, which are positive, negative, and cognitive symptoms; however, other symptoms, such as hostility, affective symptoms, or catatonic symptoms, are also described [12]. Newer guidelines also raise awareness about comorbidities, specifically substance use disorder [13] or other mental disorders along with psychical disorders when choosing a symptom-based treatment.

2.1 Positive symptoms

Positive symptoms of schizophrenia include hallucinations, delusions, disorganized thoughts, and bizarre behaviors [14, 15]. All antipsychotic medications (first, second, and newer generation antipsychotics) address positive symptoms of schizophrenia, hence the name antipsychotic.

Previously, most schizophrenia guidelines suggested second (SGA) or newer generation antipsychotics to manage positive symptoms because first-generation antipsychotics are more likely to cause severe and irreversible extrapyramidal side effects and more often lead to discontinuation than SGA [16]. However, newer studies debate whether there is a real advantage of SGA over first-generation antipsychotics.

Hence, guideline recommendations today [17] do not differentiate among antipsychotics to address positive symptoms. Treatment choices should rather consider aspects of other symptom domains, adherence, long-term functioning along with formulation, dosing, onset of effect, and half-life.

Among the antipsychotics clozapine stands out as showing better efficacy in the treatment of positive symptoms than all other antipsychotics; however, due to severe side effects, such as agranulocytosis, it is not used as first-line treatment [17]. In fact, guidelines suggest to first try two other antipsychotics before initiating treatment with clozapine. In clinical practice, this means that doctors are left with choosing any antipsychotic they prefer to address positive symptoms of schizophrenia.

2.2 Hostility

Hostility, irritability, aggressive behavior, and impulsivity are often observed in individuals with schizophrenia [18]. These behaviors can occur during both the acute and the chronic phases of the illness [18]. Hostility, broadly defined, encompasses unfriendly attitudes that manifest through overt behaviors such as irritability, anger, resentment, or aggression [18]. Clinically, it is operationalized using rating scales, such as the Positive and Negative Syndrome Scale (PANSS), which classifies hostility as a positive symptom [18].

The impact of hostility on the quality of life in individuals with schizophrenia is noteworthy; studies have consistently shown a negative correlation between hostility and overall quality of life [18]. Consequently, pharmacological treatments targeting hostility as a primary focus in managing schizophrenia have been extensively investigated in the past [18].

Multiple reviews have consistently highlighted clozapine as an effective choice for managing aggression in schizophrenia [17]. This nicely taps into the notion of hostility being regarded as a positive symptom, where clozapine has also advantages compared to other antipsychotics. Nevertheless, in clinical practice doctors are once again faced with the issue of having to try other treatments before choosing clozapine. Efficacy on hostility has been described for various treatments, including haloperidol [19], risperidone [20], olanzapine [21], cariprazine [22], asenapine, brexpiprazole, aripiprazole, lurasidone, loxapine, ziprasidone, quetiapine, iloperidone, and paliperidone. The evidence comes from post hoc analyses of clinical trials, initially conducted for regulatory purposes as well as analyses of large effectiveness trials [23, 24]. However, the generalizability of these studies may be limited since participants in these trials were not specifically selected for aggressive or hostile behavior [23, 24].

2.3 Negative symptoms

Negative symptoms play a crucial role in schizophrenia [25]. Persistent primary negative symptoms are believed to be core symptoms of schizophrenia, which are difficult to address with treatment strategies [25]. Recently, a consensus on describing negative symptoms using five key constructs, known as the “5 A’s,” has been reached [25]:

• Affect (blunted): Refers to the diminished emotional expression.

• Alogia: Characterized by reduced speech output or poverty of speech.

• Anhedonia: The inability to experience pleasure or interest in previously enjoyable activities.

• Asociality: Social withdrawal and disinterest in forming relationships.

• Avolition: A lack of motivation or initiative to pursue goals or engage in purposeful activities.

Clinically, negative symptoms are operationalized using rating scales, such as the Brief Negative Symptom Scale (BNSS) or the older Positive and Negative Syndrome Scale (PANSS) [25].

The advent of SGA initially sparked hope in addressing not only the positive symptoms of schizophrenia but also the negative and cognitive symptoms. However, therapeutic guidelines remain divided on whether SGAs truly outperform first-generation antipsychotics (FGAs) in addressing these symptoms [26]. In a recent meta-analysis [27] examining efficacy of antipsychotics on prominent and predominant negative symptoms, the authors have shown that amisulpride is better than placebo, and cariprazine is better than risperidone in addressing primary negative symptoms of schizophrenia. Amisulpride failed to show superior efficacy over other antipsychotics; so although it might address negative symptoms in untreated patients, in patients already treated with an antipsychotic it has no proven efficacy so far [27].

Cariprazine, on the other hand, has shown efficacy on primary negative symptoms in a well-designed study against risperidone [28], in another study against aripiprazole, in two real-world evidence studies [29, 30], and in several single case reports [31]. Hence, it is considered by Cerveri et al. [32] as first-line treatment for negative symptoms of schizophrenia (Figure 1) and is also endorsed as a treatment option in the EPA treatment guideline for negative symptoms [25].

Figure 1.

Treatment algorithm in predominantly negative symptoms.

2.4 Cognitive symptoms

Cognitive symptoms in schizophrenia are usually present from the onset of psychosis and are not merely side effects of antipsychotic medication [33]. Research shows that people with schizophrenia have altered brain structures, including reduced cortical thickness and gray matter volume [33]. Cognitive symptoms include [33]:

• Processing speed: Processing speed refers to how quickly an individual receives, assesses, and responds to new information. People with schizophrenia may experience slower processing speed due to disruptions in the brain’s white matter, affecting signal transmission. They might need extra time to respond, feel overwhelmed by excessive information, and require repeated instructions.

• Working memory involves temporarily retaining information to complete immediate tasks. Schizophrenia can impair working memory, affecting learning, problem-solving, and task execution.

• Attention difficulties make it hard to focus on tasks or follow conversations. Individuals may struggle with sustained attention and filtering out distractions.

• Verbal learning pertains to acquiring and retaining new information through language. Schizophrenia can hinder verbal learning, affecting memory recall and comprehension.

• Reasoning and problem-solving: These cognitive abilities involve logical thinking and solving complex problems. Schizophrenia may disrupt reasoning skills, making it harder to navigate daily challenges.

• Social cognition refers to understanding social cues, emotions, and interpersonal interactions. Individuals with schizophrenia might struggle with interpreting others’ intentions, leading to social withdrawal.

Just as negative symptoms, cognitive symptoms impact patient’s activities of daily living and reduce quality of life when present [12]. Therefore, their potential treatment could be of great benefit. In the 1990s, SGA raised hopes of addressing not only psychotic symptoms but also cognitive impairments in schizophrenia. Initial trials hinted at cognitive benefits alongside symptom control. However, subsequent research revealed that these advantages might have been influenced by trial design rather than true effects. Presently, the literature suggests that all antipsychotics yield similarly modest impacts on cognitive function [34].

2.5 Mood symptoms

Mood symptoms are common in schizophrenia and can affect the quality of life and functioning of people with this disorder [35]. Mood symptoms can include depression, anxiety, mania, or a combination of these [35]. They can occur at any stage of schizophrenia but are more likely to appear during the prodromal phase (before the onset of psychosis), the residual phase (after the acute psychotic episode), or during a relapse [36]. Mood symptoms can also be influenced by factors such as stress, substance use, medication side effects, or co-occurring medical conditions [35].

These symptoms in schizophrenia represent a treatment challenge because they can complicate the diagnosis, increase the risk of suicide, impair the response to antipsychotic medication, and reduce the adherence to treatment [37]. Therefore, it is important to assess and treat them as part of a comprehensive and individualized care plan. Treatment options may include the use of antidepressants, mood stabilizers, or anxiolytics, depending on the type and severity of mood symptoms; but antipsychotic medication that has proven benefits on mood symptoms might be first line. Presently, only quetiapine [38] and cariprazine (US only) [39] have indications in all four major psychiatric disorders: schizophrenia, bipolar mania, bipolar depression, and major depression. Olanzapine [40] alone is effective in schizophrenia and bipolar mania and can address depressed mood symptoms in combination with fluoxetine [41]. All other antipsychotics failed to show efficacy either on mania or bipolar depression of major depression—either because the studies failed or because they did not run any studies.

One of the most dangerous psychiatric symptoms that can occur is suicidality [37]. Suicide is a cause of early mortality in nearly 5% of patients with schizophrenia, and 25–50% of patients with schizophrenia attempt suicide in their lifetime [37]. Research indicates that antipsychotic medications, such as clozapine, risperidone, olanzapine, and quetiapine, may play a role in reducing mortality and suicide risk in individuals with schizophrenia [37]. In 2002, the U.S. Food and Drug Administration (FDA) specifically approved clozapine for decreasing suicide risk in patients with schizophrenia [37].

2.6 Substance use comorbidity

Dual disorder, also known as co-occurring disorder or dual diagnosis, refers to the simultaneous presence of a mental illness and a substance use disorder (SUD) [42]. This condition is associated with a higher likelihood of negative health outcomes, including increased rates of suicide, unplanned hospital admissions, and premature death [43]. The repercussions of dual disorders may extend to violence, homelessness, interactions with the criminal justice system, and the disintegration of personal relationships [43].

A staggering 75% of individuals with a severe mental health disorder are also grappling with a substance use disorder [43]. Similarly, 60% of adults with a substance use disorder are diagnosed with at least one severe mental health disorder [43]. Unfortunately, patients with dual disorders often receive incorrect diagnoses and inadequate treatment, slipping through the gaps in the healthcare system [42]. This is exacerbated by the fact that they may be turned away by both drug treatment and mental health services due to their complex needs [42].

The consequences of this neglect are profound: patients with dual disorders generally experience a diminished quality of life, along with higher mortality and suicide rates [44]. Those with schizophrenia and a substance use disorder are particularly vulnerable, facing an elevated risk of death, suicide, and other health complications [44]. Despite the critical need for comprehensive treatment, only a minority of these patients receive the necessary care [44]. Alarmingly, a mere 7% of patients with dual disorders receive treatment for both conditions, highlighting a significant gap in the current healthcare provision [44].

In terms of prevalence, 42% of individuals with schizophrenia also suffer from a substance use disorder, mostly smoking and cannabis [45]. Addressing the complexities of dual schizophrenia, which encompasses both schizophrenia and substance use disorders, presents a formidable challenge in psychiatric care [44, 46]. Although current clinical guidelines acknowledge the necessity of treating dual disorders, they offer scant direction on how to approach such cases [47]. This gap underscores the urgent need for integrated treatment strategies, which remains an unmet medical need [47].

In the realm of pharmacotherapy, first-generation antipsychotics (FGAs) are generally discouraged for treating dual disorders [48]. This recommendation stems from several detrimental characteristics associated with FGAs [48]. Notably, these drugs have been implicated in increasing cravings and self-administration of substances, such as cocaine in animal studies [48]. The pharmacological action of FGAs, particularly as dopaminergic D2 receptor antagonists, may exacerbate the situation by further diminishing the already reduced dopaminergic tone observed in drug users [48]. This significant blockade could inadvertently prompt individuals to consume greater amounts of psychoactive substances in an attempt to counteract experiences of anhedonia and cognitive deficits [48].

Therefore, contemporary guidelines and scientific literature advocate for the use of second-generation antipsychotics (SGAs) in the treatment of dual disorders [7]. Research focusing on the impact of SGAs on individuals with schizophrenia, who also consume cannabis or alcohol, has identified aripiprazole as the most frequently utilized medication [7]. It is important to recognize that aripiprazole’s effectiveness may be indicative of a broader class effect associated with dopamine partial agonists [7].

Dopamine partial agonists or third-generation antipsychotics (TGAs), such as aripiprazole, cariprazine, and brexpiprazole, offer potential therapeutic benefits for treating both psychosis and substance use disorders (SUD) [7]. Among the partial agonists and in fact, among all other antipsychotics, cariprazine has the highest binding affinity to the D3 receptors in the brain [49]. Substance abuse has been linked to the upregulation of D3 receptors, with studies showing that repeated exposure to drugs can lead to a selective increase in D3 receptor expression [50]. This is evident in D3 receptor knockout (D3-KO) mice, which, unlike their wild-type counterparts, exhibit a heightened propensity for self-administering heroin and cocaine, along with an increased motivation for drug-seeking behavior [50]. The role of D3 receptors in addiction is further highlighted by the fact that antagonists or partial agonists targeting these receptors have been found to diminish the motivation for psychostimulant seeking in various animal models of relapse [50]. Cariprazine stands out in this context as it possesses both partial agonist properties and high affinity for D3 receptors [49]. Remarkably, cariprazine’s affinity for D3 receptors surpasses that of dopamine itself by three orders of magnitude and all other antipsychotics currently in use [49].

This unique binding profile is theorized to enhance cariprazine’s effectiveness in treating negative symptoms and may be beneficial for addressing issues related to cognition, mood, emotions, and reward mechanisms, which are particularly relevant in the context of substance use [49]. Given these pharmacological profiles, Martinotti et al. recommend the use of dopamine partial agonists as the first-line treatment in maintenance settings for dual disorders [7]. Notably, the effectiveness of cariprazine in preventing substance abuse is approximately 20 times greater than that of aripiprazole, underscoring its significant promise as a treatment option in the context of addiction and dual disorders [51].

2.7 Catatonic symptoms

Catatonia is a multifaceted psychomotor syndrome that was once considered a subtype of schizophrenia [52]. However, following revisions in the DSM-5, it can now be categorized as arising from various other mental health conditions [52]. These include brief psychotic, schizophreniform, and schizoaffective disorders or substance use [52]. Its symptoms are a distinct set of behaviors observed in individuals with schizophrenia [52]. These include [52]:

• Stupor: This state resembles near unconsciousness. The person becomes unresponsive, immobile, and lacks awareness of their surroundings.

• Catalepsy: Individuals experience trance-like seizures characterized by rigid body posture. They may hold unusual positions for extended periods.

• Waxy flexibility: A peculiar phenomenon where the limbs remain in the position someone else puts them in. It is as if the person’s body is malleable like wax.

• Mutism: Lack of verbal response, catatonic individuals may not speak or communicate effectively.

• Negativism: A tendency to resist or oppose external stimuli or instructions. For instance, they might refuse to move when asked.

• Posturing: Catatonic patients exhibit unusual body postures that defy gravity. These positions can be sustained for extended periods.

• Mannerism: This involves displaying odd and exaggerated movements, gestures, or expressions.

• Stereotypy: Repetitive, purposeless movements without an apparent reason. These actions can persist for minutes, hours, or even days.

Interestingly, although catatonia might be a form of schizophrenia, it is not treated primarily with antipsychotics [52, 53]. Treatment includes the administration of benzodiazepines, such as lorazepam or alternatively electroconvulsive therapy (ECT) [52, 53]. Antipsychotics should be evaluated for their potential to induce catatonic symptoms and discontinued if possible [52, 53]. There is some ambiguity about the role of antipsychotics, but it is generally encouraged to discontinue treatment in patients presenting with catatonia [52, 53].

3. Longitudinal treatment aspects

The longitudinal treatment approach recognizes schizophrenia as a chronic condition, necessitating long-term management. It accounts for schizophrenia management from the prodromal phase to the first occurrence of acute symptoms to sustained stability, functional improvement, rehabilitation, and improvement of quality of life (Figure 2). Different stages need different treatment considerations, and while in the acute phase, the most important is effective symptom control, on long-term safety and quality of life considerations shift more into focus.

Figure 2.

Aspects of longitudinal treatment in schizophrenia.

Schizophrenia treatment in general starts with the onset of acute symptoms and acute psychosis. While the prodromal phase precedes this acute stage, antipsychotic treatment typically is not initiated this early. However, once acute symptoms appear, swift intervention becomes crucial due to the significant impact of the duration of untreated psychosis (DUP) on overall outcomes [54, 55]. DUP represents the time span between the onset of psychotic symptoms and the commencement of treatment. Prioritizing DUP reduction becomes a critical strategy, especially for managing first-episode psychosis [54, 55]. Detecting and addressing symptoms promptly are essential. Notably, extended DUP has been associated with less favorable prognoses [54, 55]. It serves as a predictor for the likelihood and extent of recovery, while early treatment offers promise for long-term well-being [54, 55]. Research consistently underscores the effects of prolonged DUP on individuals experiencing their initial psychotic episode. Longer DUP correlates with more severe positive symptoms (such as hallucinations and delusions) and lower rates of symptom remission [54, 55]. Furthermore, extended DUP is linked to impaired social cognition, impacting interpersonal relationships and overall functioning [54, 55]. Addressing DUP promptly becomes pivotal in enhancing outcomes and improving the quality of life for individuals navigating the complexities of psychosis [54, 55].

During the acute phase of schizophrenia, managing the prevailing symptoms takes priority [36]. These symptoms primarily involve positive symptoms, alongside potential hostility and self-harm [36]. However, as the course of schizophrenia unfolds, symptomatology evolves [36]. Negative symptoms, cognitive impairments, and mood disturbances become more pronounced, necessitating treatment adjustments [36]. An ideal approach considers both immediate and long-term treatment needs of schizophrenic patients [36]. Notably, altering treatments during stable phases carries a substantial risk of relapse, emphasizing the importance of thoughtful decisions [56]. Therefore, the right treatment choice balances short-term efficacy with long-term symptom control and safety from the start. Taking sedation as an example, antipsychotics’ sedative effects during the first stages of treating acute psychosis can be therapeutically beneficial for agitated patients [8, 57]. Patients who are having trouble sleeping may also benefit from bedtime sedation [8, 57]. Unwanted daytime sedation, on the other hand, may have a detrimental influence on recovery, impeding the positive effects of psychosocial training, psychiatric rehabilitation, and other treatments [8, 57]. It is linked to long-term detrimental effects on cognitive function and metabolic changes, including weight gain [8, 57]. Persistent sedation can affect social, recreational, and occupational functioning [8, 57]. It can cause daytime sleepiness, longer sleep durations, and decreased cognitive sharpness [8, 57].

As schizophrenia evolves, relapse, remission, and overall safety considerations move into focus and become a cornerstone of compassionate care. Relapse among patients with schizophrenia carries profound implications. It results in the deterioration of symptoms, compromised functioning, cognitive decline, and a diminished quality of life [58]. This downward trajectory places a substantial burden on both patients and their families, causing emotional distress and financial strain [58]. Consequently, preventing relapse becomes a paramount therapeutic objective [58]. In real-world scenarios, hospitalization often serves as an indirect measure of relapse [58]. When patients require hospital care, it signifies a significant worsening of symptoms [58].

Numerous factors contribute to the risk of relapse, including nonadherence to antipsychotic medications, stress, depression, and substance misuse [58]. The Role of Continuous Antipsychotic Treatment: Consistent use of antipsychotic medications is associated with reduced hospitalization frequency and duration [58]. In summary, relapse remains a recurring challenge in schizophrenia management, transcending mere symptomatology [58]. Timely detection, intervention, and sustained treatment are pivotal for improving outcomes and enhancing the overall well-being of individuals navigating this intricate disorder [58].

A standardized definition of remission criteria was proposed by the International group led by Dr. Nancy Andreasen in 2005 [59]. It involves a low symptom threshold for the eight core symptoms (both positive and negative) on the Positive and Negative Syndrome Scale (PANSS) for at least 6 consecutive months [59]. Remission not only sets a standard for minimal symptom severity (resolution) but also specifies how long symptoms must remain at this minimal level (6 months) [59]. Individuals who achieve remission experience better subjective well-being [59]. Reduced symptoms contribute to an improved quality of life [59]. Remission is associated with better functional outcomes compared to those who do not achieve it [59]. Research suggests that remission can be attained in 20–60% of people with schizophrenia. Remission serves as a useful way to monitor improved health. Clinicians often use the Andreasen Consensus Group criteria to assess remission in clinical practice. Achieving remission involves not only symptom reduction but also maintaining this state over time. Balancing short-term symptom control with long-term stability is crucial. Remission reduces the burden on patients, families, and healthcare systems. It minimizes hospitalizations, improves functioning, and enhances overall well-being. Overall, it is established that remission duration is predicted by negative, positive, and cognitive symptom control, treatment dosage, and duration of illness [60]. Hence, antipsychotics addressing negative and cognitive symptoms might have advantages.

Finally, accounting for safety aspects protects patients from harm, provides a stable foundation for therapeutic interventions, and fosters trust between patients and caregivers [61, 62, 63, 64]. This trust is crucial as it encourages adherence to treatment plans and promotes open communication about symptoms, side effects, and concerns [61, 62, 63, 64]. Moreover, considering safety aspects is vital in mitigating risks associated with the condition itself, such as vulnerability to self-harm or the potential for unpredictable reactions to medication [61, 62, 63, 64]. Especially, since 86–98% of patients report experiencing side effects that are often viewed as being worse than the positive symptoms of psychosis [65, 66, 67].

Schizophrenia patients often harbor fears and concerns related to specific side effects of antipsychotic medications [68, 69]. Weight gain is a common worry as it can impact self-esteem, physical health, and overall well-being [68, 69]. Extrapyramidal symptoms (EPS), which encompass tremors, muscle stiffness, and abnormal movements, are also a concern, along with restlessness or an inability to sit still [68, 69]. Although tardive dyskinesia is less frequent with newer antipsychotics, it is still a worry to patients as it is highly stigmatizing [68, 69]. Excessive sleepiness or drowsiness can disrupt daily activities and productivity, hence patients feel very bothered when they occur [68, 69]. Elevated prolactin levels may lead to abnormal breast milk production (galactorrhea) and other hormonal imbalances, including sexual dysfunction [68, 69]. Furthermore, some antipsychotics can cause cognitive dullness or difficulty thinking clearly, which can be distressing for patients [68, 69]. Doctors share similar apprehensions. When making treatment decisions, they aim to prevent relapse while minimizing side effects such as cardio-metabolic symptoms, severe EPS, anticholinergic effects, and cognitive blunting. Prioritizing safety in schizophrenia treatment underscores a commitment to holistic, patient-centered care, recognizing the unique challenges faced by individuals living with this condition.

Two recent large-scale meta-analysis studies, comparing the efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the acute and maintenance treatment of adults with schizophrenia found no clear differences between antipsychotics in addressing acute symptoms of schizophrenia or in their ability to prevent relapse [3, 70]. Authors, therefore, proposed that the main consideration when choosing an antipsychotic for ongoing treatment should be its tolerability [3, 70]. Authors compared different safety concerns such as EPS, weight gain, sedation, QT prolongation, etc. among antipsychotics and concluded that in most aspects, newer generation antipsychotics such as partial dopamine agonists (aripiprazole, brexpiprazole, cariprazine) and lurasidone performed better on safety parameters [3, 70]. First-generation antipsychotics, primarily antagonists such as haloperidol, often result in noticeable extrapyramidal side effects, while older second-generation antipsychotics frequently lead to weight gain—a concern due to its potential impact on cardiovascular health and diabetes risk [3, 70]. In contrast, aripiprazole and cariprazine were comparable to placebo in their potential to cause weight gain on long term, and all three partial agonists (aripiprazole, brexpiprazole, cariprazine) had no issues with causing hyperprolactinemia [70]. In the past, treatment of hyperprolactinemia was primarily recommended for symptomatic patients [71]. However, recent insights have highlighted that persistent asymptomatic hyperprolactinemia can lead to long-term complications, including osteoporosis and breast cancer [71]. Consequently, it is crucial to manage hyperprolactinemia even if it is asymptomatic at the time of initial detection [71]. This can be done by reducing the dose of antipsychotic medication, switching to a prolactin-sparing antipsychotic, or adding a dopamine partial agonist to the treatment regime [71].

4. Combination strategies

Antipsychotic polytherapy (APP), involving the use of multiple antipsychotic medications, is utilized for approximately 20–30% of patients undergoing antipsychotic therapy [72]. However, APP is not universally applicable for all cases of antipsychotic treatment [72]. The NICE, UK, Clinical Guidelines provide a framework for considering APP, suggesting it as a potential option following the failure of two or more antipsychotic monotherapy (APM) trials and subsequent clozapine (CLZ) monotherapy [72]. The transition to APP should be gradual with careful monitoring at each stage, and should consider the pharmacological profiles of the antipsychotic drugs involved [72]. A key focus is on optimizing dopamine D2 receptor occupancy and leveraging other receptor categories or subtypes to achieve a more favorable balance between efficacy and adverse events (AE) [72].

A review and meta-analysis of the literature indicated that APP may be superior to monotherapy in open-label studies of lower quality [72]. However, this superiority is not consistently supported in high-quality, double-blind, and randomized studies [72]. These studies suggest that enhanced efficacy with APP is limited to specific strategies rather than a general advantage over monotherapy [72]. Notably, the combination of two first-generation or second-generation D2 antagonists did not show superiority, but the addition of partial dopamine agonists did [72].

One possible treatment option to cover the acute and long-term needs of schizophrenia is to combine AP, which is classically perceived as highly effective, dopamine antagonists (haloperidol, olanzapine, risperidone, clozapine or LAI) with a dopamine partial agonist. Thereafter, when the acute symptoms improve a slow down-titration of the antagonist can be evaluated leaving patients with the well tolerable long-term partial agonist medication. The choice of the partial agonist should be based on individual treatment needs and should also consider long-term symptoms such as negative, addiction, and mood symptoms.

5. Conclusion

This review’s objective was to examine the literature concerning acute (symptom based) and long-term (safety based) treatment aspects of schizophrenia. In summary, clozapine was superior to all other antipsychotics in addressing positive symptoms of schizophrenia along with hostility, however, is not a first-line treatment drug due to its severe side effects. Besides, clozapine no other antipsychotic differed in its efficacy on positive symptoms, so treatment choices may vary. One way to influence this treatment choice is to look at the other symptom domains. Concerning negative symptoms cariprazine outperformed risperidone. No other antipsychotic could show efficacy on primary negative symptoms in comparison with another antipsychotic. Cariprazine further, along with quetiapine and olanzapine/fluoxetine, can address mood symptoms of various mood disorders such as mania, bipolar depression, and major depression, which makes these drugs a good treatment choice if mood symptoms of schizophrenia are present. Further, if comorbid substance use is present, partial agonists (aripiprazole, brexpiprazole, and cariprazine) are choice of treatment, with an advantage of cariprazine due to its D3 mechanism of action, which also plays an important role in substance use. Although cognition is an important aspect to maintain and not worsen in schizophrenia, evidence suggests no difference between the antipsychotics in their efficacy to improve cognition. A tabulated summary is provided below in Figure 3.

Figure 3.

Tabulated summary of findings.

Considering long-term aspects, no antipsychotic was better than the other in preventing relapse or achieving remission. Differences were rather modest and treatment choice should be led by considerations of tolerability. Here, first-generation antipsychotics mostly cause severe EPS, while most second-generation antipsychotics cause weight gain, hyperlipidemia, sedation, or prolactin increase. Newer generation antipsychotics, among them also the partial agonists cause less side effects and are often favored by doctors and patients.

Combining different antipsychotics is a well-established practice in psychiatry. Combinations should consider complementary efficacy and reduced safety concerns by, for example, reducing doses.

Overall, a careful consideration should be applied when choosing treatment accounting for prevalent symptoms, longitudinal aspects, along with psychiatric and somatic comorbidities, as well as preference of patients—this is what a patient-centered treatment is all about!

Acknowledgments

Authors would like to thank their mentor Dr. György Németh for his continued support.

Conflict of interest

Authors are all co-workers of Gedeon Richter Plc.