Antipsychotic-induced sensitization and tolerance: Behavioral characteristics,developmental impacts,and neurobiological mechanisms

Introduction

Antipsychotic drugs are the primary medications for the treatment of schizophrenia and other neuropsychiatric disorders with a psychosis component (e.g. amphetamine psychosis, psychosis in Alzheimer’s disease, psychosis in Parkinson’s disease, etc.). Since the introduction of chlorpromazine in psychiatry in 1952, about 50 additional antipsychotic drugs have been developed for the treatment of schizophrenia. They are all significantly more effective than placebo and are often classified into two groups, typical (or first generation) and atypical (or second generation), with atypical drugs offering a reduced risk of extrapyramidal motor syndromes (EPS) (Kapur and Remington, 2001), although recent studies have questioned the validity of such a classification system (Leucht et al. 2013). The differences in efficacy among various commonly prescribed antipsychotic drugs are small yet robust, with clozapine being more efficacious than all the other drugs (e.g. amisulpride, olanzapine, risperidone, paliperidone, zotepine, haloperidol, quetiapine, aripiprazole, etc.).

Much research on antipsychotic drugs has four interconnected goals in mind. The first one is to understand the mechanisms of action of antipsychotic drugs at various levels (e.g. molecular, cellular, neural network, and behavioral) in an attempt to answer the basic question of how antipsychotic drugs work to achieve their therapeutic effects (Kapur, 2003, Kapur et al., 2005). There have been attempts to link actions of antipsychotic drugs at various receptor sites, notably dopamine D₂, serotonin (5-HT)_2A, and 5-HT_1A receptors (Kapur et al., 2003; Meltzer et al., 1989; Richtand et al., 2007; Seeman, 2000) to their behavioral mechanisms of actions (Li et al., 2007). The second goal is to enhance our understanding of etiology and psychopathological mechanisms relevant for psychosis. The rationale is that dysfunction of the molecular targets of antipsychotic drugs such as D₂ and 5-HT_2A can be a possible cause of psychotic symptoms (Seeman, 2008). The third one is to provide better assays for new drug discovery. With the increase of our understanding of etiology of psychosis, molecular and behavioral mechanisms of antipsychotic action, behavioral and molecular assays with better predictive validity could be developed to identify new compounds useful for psychosis (Allen et al., 2011). The final one, which falls in the domain of behavioral neuroscience, is to use antipsychotic drugs as pharmacological tools to probe the neurochemical basis of behavior, as typical antipsychotic drugs such as haloperidol are potent D₂ receptor antagonists and atypical drugs possess dual actions against serotonin 5-HT_2A and dopamine D₂ receptors. Research discussed in this review has been largely aimed at the first goal.

One important feature associated with repeated or chronic antipsychotic treatment is the alterations of drug sensitivity, a phenomenon largely ignored in the field of behavioral pharmacology in recent decades. In comparison to extensive research on changes of drug sensitivity induced by psychotomimetic drugs (e.g. amphetamine, cocaine and PCP etc.) (Pierce and Kalivas, 1997; Robinson and Becker, 1986), antipsychotic-induced alterations are not as well understood. This situation is peculiar given the fact that antipsychotics, like drugs of abuse, are often taken repeatedly by people for a prolonged period of time, and increase in antipsychotic response is thought to be an important mechanism supporting the maintenance of antipsychotic effect (Kapur et al., 2006). One of the major issues which may have contributed to this lack of attention is the difficulty in demonstrating its existence consistently. For example, in animal studies using the prepulse inhibition paradigm, alterations in antipsychotic drug sensitivity have never been consistently established among different antipsychotics (Geyer et al., 2001; Li et al., 2011). On the other hand, clinical studies often focus on the efficacy, tolerability, and side effect profiles of individual drugs, overlooking the temporal course of changes in drug sensitivity. Also, changes in antipsychotic efficacy in human studies typically do not become apparent within a limited trial period. It often requires years of medication in order to induce such a change (e.g. supersensitivity psychosis, tardive dyskinesia (TD)).

Several years ago, when we started looking into this issue, there were limited and scattered reports. There was also a lack of terminology used to describe drug-induced long-term changes in drug sensitivity and no standardized approach to study these changes. Current psychiatrists and psychopharmacologists do not talk about long-term antipsychotic effects in these terms, let alone discuss their clinical implications. We thus borrowed two terms from the literature of drugs of abuse and defined “antipsychotic sensitization” and “antipsychotic tolerance” as reflecting the increased and decreased drug effects due to past drug use, respectively. Antipsychotic sensitization and tolerance reflect the long-term consequences of chronic antipsychotic drug treatment on the brain and behavioral functions and are thought to be mediated by drug-induced changes in neuroplasticity and basic psychological processes. Therefore, understanding the behavioral characteristics and neurobiological underpinnings of antipsychotic sensitization and tolerance should greatly enhance our understanding of mechanisms of antipsychotic action, and may help future drug discovery and improve clinical treatment of schizophrenia. This understanding may also provide a different perspective of looking at some clinical effects. For example, antipsychotic sensitization and tolerance may explain why some recent clinical trials of promising novel therapeutics fail to demonstrate efficacy (Gill et al., 2014). The testing of novel compounds is often done in patients exposed to antipsychotic drugs (comparators) for years and briefly withdrawn. Due to the (cross)-tolerance effect, it is possible that prior antipsychotic exposure history and subsequent withdrawal affects the response of the brain to novel drugs to the extent that it effectively masks the true efficacy of novel compounds. On the other hand, as clinical responses of patients on novel compounds are often compared to those on treatment-as-usual (TAU) after a brief washout period. Re-exposure to the same drug may potentiate the TAU group’s clinical responses to the comparator drug, masking the true efficacy of novel compounds from another perspective. In addition to these implications for antipsychotic drug research, because antipsychotic sensitization and tolerance share many similarities with behavioral sensitization and tolerance induced by other psychoactive drugs such as psychostimulants (e.g. amphetamine, methamphetamine, nicotine, etc.), opioids, and dissociative anesthetics (e.g. phencyclidine, ketamine, MK-801) (Poulos et al., 1981; Robinson and Becker, 1986), studies of antipsychotic sensitization and tolerance could expand our understanding of sensitization and tolerance phenomena in general, and introduce new research ideas, tools, approaches, and knowledge.

This review will provide an overview of recent research in this area. We will focus on animal work that examines the behavioral characteristics of antipsychotic sensitization and tolerance, the possible underlying neurobiological mechanisms, their developmental impacts and clinical implications. To show the clinical relevance of these phenomena, human studies on antipsychotic sensitization and tolerance will be briefly reviewed at the beginning. It should be noted that sensitization and tolerance can develop in various domains involving different organ systems (e.g. cardiovascular, liver, blood, endocrine, brain, etc.) (Diamond and Borison, 1986; See and Kalivas, 1996). Because the behavior and associated brain functions are the focal targets of antipsychotics, we will restrict our use of antipsychotic sensitization and tolerance in the behavioral domain. Thus, we define antipsychotic sensitization as the consequence of repeated drug treatment that leads to increased behavioral effects of a drug, while antipsychotic tolerance as the decreased behavioral effects.

General issues

It is worth mentioning three general principles at the outset. Readers who are familiar with behavioral sensitization and tolerance associated with drugs of abuse can easily recognize them. First, sensitization and tolerance develop to the specific effects of a drug, not to a drug itself. Like many psychoactive drugs, antipsychotic drugs typically have multiple behavioral and physiological effects due to their complex pharmacodynamic receptor actions (Miyamoto et al., 2005). It is thus possible that antipsychotic sensitization and tolerance may develop to one effect of a drug, but not to another (Sun et al., 2009). It is also possible that sensitization is seen in one effect while at the same time tolerance is seen in others. Furthermore, the same drug may induce sensitization to a drug effect under some circumstances (e.g. dosage level, dosing regimen, and duration) but may induce tolerance to the same effect under other conditions (Stewart and Badiani, 1993). The second point is that multiple processes and mechanisms are involved in the development of antipsychotic sensitization and tolerance. At the behavioral level, antipsychotic sensitization and tolerance reflect a general nonassociative learning and memory process in which an organism modifies its responses to an exogenous stimulus (e.g. a drug) based on its past experience with this stimulus. The learning and memory processes involved in antipsychotic sensitization and tolerance are not dissimilar to those involved in the basic forms of habituation and sensitization. Because the induction and expression of both effects depend on the context in which drug treatment occurs and on the specific motoric response that the drug targets (Feng et al., 2013; Poulos and Hinson, 1982; Sun et al., 2014; Zhang and Li, 2012), other associative processes (e.g. conditioning, drug-setting, behavioral response) may also play a role in the development of antipsychotic sensitization and tolerance. At the brain level, drug-induced plastic changes on receptor density, intracellular signaling, electrophysiological property of neurons, and neuroanatomic volume are examples of many processesthat antipsychotic sensitization and tolerance exert on. Goudie (1993: 313) suggested that all these different processes and mechanisms associated with behavioral sensitization and tolerance can be classified into two general categories: “higher level mechanisms involving instrumental and classical conditioning processes, and more molecular mechanisms involving functional and dispositional adaptations.” He also pointed out that it would be easier to “derive general “laws” of sensitization and tolerance at the level of the first class rather than the second.” The third point is that many experimental and pharmacological factors influence the development of antipsychotic sensitization and tolerance. Notable factors include treatment schedule, drug dose, and behavioral testing conditions (Barnes et al., 1990; Remington and Kapur, 2010). Under some conditions, these factors could even determine whether a sensitization or tolerance will be developed (Klein and Schmidt, 2003; Poulos et al., 1981). With these points in mind, we will first review some human studies that examined antipsychotic sensitization and tolerance and their roles in explaining therapeutic and side effects of antipsychotic treatment.

Clinical phenomena associated with antipsychotic sensitization and tolerance

Like other psychoactive drugs, antipsychotic drugs are known to induce various clinically relevant sensitization and tolerance effects in many behavioral domains, including both therapeutic and side effects (Emmett-Oglesby and Goudie, 1989), resulting from the brain’s adaptive responses to the bombardment of long-term antipsychotic drug treatment (Konradi and Heckers, 2001; Schmitt et al., 2004). The observations that psychotic symptoms improve over time and extrapyramidal side effects get worst after years of medication could be considered examples of antipsychotic sensitization. On the other hand, chronic antipsychotic treatment can also induce tolerance in certain behavioral domains, as evidenced by the findings that in comparison to patients with chronic antipsychotic treatment, first-episode schizophrenia patients respond to lower doses of antipsychotics; are more sensitive to side effects; and have comparatively higher response rates than chronic schizophrenia patients (Lieberman et al., 1993; Kapur et al., 2000). These differences between drug naïve (first-episode) and drug experienced patients could be interpreted as a result of tolerance developed in the drug experienced group. The same drug treatment may induce sensitization in some patients, but tolerance in others (Sramek et al., 1990). Admittedly, the terms “antipsychotic sensitization” and “antipsychotic tolerance” have not been frequently used in describing many clinical phenomena. The above mentioned clinical phenomena could also be subject to other interpretations. However, as will become apparent, classifying antipsychotic phenomena in the framework of sensitization and tolerance would provide a unified theory (the brain’s adaptation responses to the bombardment of long-term antipsychotic drug treatment) to better understand their underlying mechanisms. In this section, the four best known phenomena consistent with the conceptualization of antipsychotic sensitization and tolerance will be selectively reviewed, including: exponential time course of symptom improvement, time-dependent sensitization (TDS), supersensitivity psychosis, and TD (Agid et al., 2003; Fallon and Dursun, 2011; Kapur et al., 2006).

Preclinical evidence for antipsychotic-induced behavioral sensitization and tolerance

Sensitization and tolerance induced by antipsychotic drugs have a long research history. The first report of antipsychotic tolerance in English that can be found on the PubMed database is a study by Boyd (1960) who reported that Wistar rats developed tolerance to the motor suppressant and lethal effects of chlorpromazine over a period of 40 weeks when they were injected with increasing daily doses of chlorpromazine. Stille et al. (1971) also reported that tolerance occurred to repeated dosing with clozapine (2.5–20 mg/kg, p.o) and thioridazine (5–20 mg/kg, p.o), but not to haloperidol or perphenazine in locomotor activity in mice. At the end of the 19 days of drug administration, clozapine, and thioridazine even caused an increase in locomotor activity, a sign of behavioral supersensitivity (Seeman et al., 2005). On sensitization, Antelman et al. (1986: 58) reported that a single injection of low, clinically relevant doses of haloperidol and fluphenazine hydrochloride causes catalepsy in rats that grows over time “such that one re-exposure to the same compound up to 8 weeks later results in a marked enhancement (i.e. sensitization) of this response.”

Over the years, many preclinical studies provide strong support for chronic antipsychotic-induced sensitization and tolerance (Antelman et al., 1986). For example, intermittent haloperidol treatment via daily injection is shown to cause a progressively potentiated catalepsy (Amtage and Schmidt, 2003), enhanced vacuous chewing movements (VCMs, a proxy for tardive dyskinesia in humans) over time (Turrone et al., 2003), enhanced suppression of milk intake (Wolgin and Moore, 1992), enhanced disruption of conditioned avoidance responding (CAR) (Li et al., 2007), enhanced impairment of reward-based lever pressing rates (Trevitt et al., 1998; Varvel et al., 2002), enhanced disruption of maternal behavior (Zhao and Li, 2009b), and enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion (Sun et al., 2009). A similar effect on the PCP-induced hyperlocomotion has also been found with repeated clozapine and olanzapine treatment (Sun et al., 2009). In addition, repeated clozapine treatment is also shown to induce increasing numbers of myoclonic seizure-like jerks in rats (Stevens et al., 1997). Finally, Kaempf and Porter (1987) demonstrated sensitization for the rate-suppressing effects of the typical antipsychotic pimozide.

With regards to the antipsychotic-induced tolerance, continuous haloperidol treatment via osmotic mini-pump has been shown to cause a progressively decreased inhibition of spontaneous motor activity in rats (Carey and Deveaugh-Geiss, 1984), increased behavioral supersensitivity, as measured by increased amphetamine-induced locomotor activity following antipsychotic discontinuation (Samaha et al., 2007), and a progressively decreased disruption of avoidance responding over time (Samaha et al., 2008). Stanford and Fowler (1997) reported that clozapine-treated rats exhibited tolerance to the drug’s suppressive effect on the amount of time that rats were in contact with a force-sensing target disk. Trevitt et al. (1998) found that repeated injections of clozapine, but not haloperidol enhanced its suppression of lever pressing in a fixed ratio 5 (FR-5, 5 presses result in one reward). Porter and colleagues have conducted a series of experiments to identify differences between the acute and subchronic effects of antipsychotic drugs on operant responding in rats. In one earlier study, they demonstrated that acute treatment with clozapine significantly suppressed operant response rates on fixed-interval 60-second responding. With repeated drug administration and testing, the clozapine-treated rats gradually developed tolerance to the drug effects and recovered back to the vehicle control levels after seven days of drug treatment (Kaempf and Porter, 1987). Later, their group reported that although acute clozapine (10 mg/kg) significantly disrupted response rates and reinforcement rates and significantly increased response duration on a schedule of multiple random interval responding for food reinforcement, chronic administration of clozapine resulted in a development of tolerance (Villanueva and Porter, 1993). Varvel et al. (2002) also found that repeated clozapine produced a decrease in the rate of responding for food reward under a multiple FR 30/ fixed-interval (FI) 60-second schedule. More importantly, the degree to which clozapine tolerance develops appears to depend in part on the schedule of reinforcement, with more complete tolerance observed under a FI 60-second schedule (Kaempf et al., 1987), and only partial tolerance (approximately 50–75%) under a FR 30 schedule (Varvel et al., 2002; Villanueva et al., 1993). This differential tolerance was attributed to the different baseline levels of responding generated by these reinforcement schedules (Varvel et al., 2002). Clozapine-induced tolerance has also been observed in a drug discrimination task (Goudie et al., 2007) and rat maternal behavior (Zhao and Li, 2009b). Taken together, antipsychotic sensitization and tolerance appear to be inevitable features associated with repeated drug treatment. Therefore, understanding the neurobiological and behavioral factors that modulate the induction and expression of sensitization/tolerance is expected to greatly enhance our understanding of the effects of clinical treatment.

As mentioned above, antipsychotic sensitization refers to the increased behavioral responsiveness to an antipsychotic drug due to past drug treatment history, while tolerance refers to the opposite behavioral pattern (i.e. decreased responsiveness). In recent years, we developed a two-phase paradigm to study antipsychotic sensitization and tolerance. In the induction phase, different groups of animals are being repeatedly treated with various doses of an antipsychotic drug or vehicle for 3–7 days and tested in a behavioral model of antipsychotic activity (e.g. the conditioned avoidance response model) daily. In the expression phase, all animals are being challenged with a single dose of the drug and their performance in the test is compared. The magnitude of antipsychotic sensitization and tolerance can be measured in two ways in both phases (Qin et al., 2013; Swalve and Li, 2012), similar to the ones used in the behavioral sensitization induced by psychostimulants (Browman et al., 1998). The first index of antipsychotic sensitization or tolerance is revealed through a within-subjects comparison in the induction phase during which the behavioral effect of the drug is either stronger or weaker on the last day of drug treatment than that on the first day (e.g. a comparison between days 1 vs 5) (Zhang and Li, 2012). A second index is derived from a between-subjects comparison in the expression phase during which the behavioral responses of drug-pretreated and vehicle-pretreated animals are compared. With a between-groups analysis, antipsychotic sensitization or tolerance is indicated if drug-pretreated animals show a significantly greater or lower sensitivity to the drug challenge than vehicle-pretreated animals. Overall, it is believed that a between-subjects analysis provides a more “conservative” index of sensitization or tolerance (Browman et al., 1998), as this approach ensures that variables that could contribute to potential changes in behavior are present in both the drug and vehicle control groups. In some cases, the behavior affected by an antipsychotic drug (as an index of antipsychotic effect) is allowed to recover under the drug-free condition to the pre-drug and vehicle control level before the drug challenge, thus, any group difference found on the challenge test could only be attributed to past drug treatment history. This approach provides the strongest demonstration of antipsychotic sensitization and tolerance. Figure 1 illustrates such an approach in the conditioned avoidance response test of antipsychotic drugs.

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Figure 1.

A schematic depiction of the two-phase paradigm used to study antipsychotic sensitization and tolerance. In the induction phase, different groups of animals are being repeatedly treated with various doses of an antipsychotic drug or vehicle for 3–7 days and tested in a behavioral model of antipsychotic activity daily. Antipsychotic sensitization or tolerance is revealed through a within-subjects comparison in this phase during which the behavioral effect of the drug is either stronger or weaker on the last day of drug treatment than that on the first day. In the expression phase, all animals are being challenged with a single dose of the drug and their performance in the test is compared. Antipsychotic sensitization or tolerance is indicated if drug-pretreated animals show a significantly greater or lower sensitivity to the drug challenge than vehicle-pretreated animals.

It is well established that at clinically relevant doses, all clinically approved antipsychotic drugs acutely suppress avoidance responding without altering unconditioned escape response in rats (Arnt, 1982; Wadenberg et al., 2001). Thus, the magnitude of avoidance suppression is frequently used as a validated behavioral index of antipsychotic activity (Arnt, 1982; Bignami, 1978; Shannon et al., 1999; Van Der Heyden and Bradford, 1988; Wadenberg and Hicks, 1999). As Figure 1 shows, in the induction phase, antipsychotic sensitization or tolerance in this test is observed when the avoidance-disruptive effect of the drug increases or decreases in magnitude throughout the treatment period. In the expression phase, sensitization or tolerance is shown when the drug-treated animals exhibit a lower or higher avoidance response than those treated with vehicle (Li et al., 2010). Several early studies have demonstrated both effects in the conditioned avoidance response test. For example, Fregnan and Chieli (1980) found that the anti-avoidance effect of haloperidol started on the first testing day and was progressively enhanced with each subsequent drug administration (across-session decline in avoidance responding). It reached a maximum level within 5–8 days. Kuribara and Tadokoro (1981) and Beninger et al. (1983) confirmed this finding and extended it to two other classes of antipsychotics, YM-08050, YM-08051 and pimizode respectively. Using a home-cage control group injected with drugs but not tested repeatedly for avoidance responding, they also showed that the across-session decline in avoidance responding was not due to the accumulation of the drugs with repeated dosing. Sanger (1985) showed that repeated administration of clozapine over four days induces a strong tolerance to the avoidance-disruptive effect of clozapine. It should be noted that many previous studies on antipsychotic sensitization and tolerance have not paid enough attention to the distinct processes of the induction and expression. Most of them only focused on the induction process. Figure 2 shows the results of haloperidol sensitization in the conditioned avoidance response model in adult rats (Swalve and Li, 2012). The sensitization pattern is clearly demonstrated in both phases.

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Figure 2.

(a) Effect of repeated haloperidol (HAL) treatment (0.025 mg/kg, sc, -60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats on the final training day (drug-free), five days of drug exposure and two drug-free retesting sessions are expressed as mean+standard error of the mean (SEM). Rats received either 0, 1, 2, 3, 4, or 5 days of HAL according to their group, *p<0.05. (b) Effect of number of drug exposure days on final challenge day. All groups were injected with HAL (0.025 mg/kg) and avoidance responses were measured, *p<0.05. Adapted from Swalve N and Li M (2012) Parametric studies of antipsychotic-induced sensitization in the conditioned avoidance response model: Roles of number of drug exposure, drug dose, and test-retest interval. Behav Pharmacol 23: 380–391 with permission from Wolters Kluwer Health, Inc.

Similarly, it is possible to apply this basic paradigm to other behavioral tests of antipsychotic drugs. For example, the same paradigm has been used to demonstrate that repeated administration of olanzapine (also, risperidone, asenapine) or clozapine induces a potentiated (sensitization) or a decreased (tolerance) inhibition of the PCP-induced hyperlocomotion, respectively (Feng et al., 2013; Qin et al., 2013; Sun et al., 2009; Zhang and Li, 2012; Zhao et al., 2012), another preclinical test for antipsychotic activity (Gleason and Shannon, 1997) (see Figure 4(a)). Furthermore, this paradigm could also be used to conduct cross-sensitization or cross-tolerance studies by challenging animals with a different antipsychotic drug during the expression phase. As an example, Zhang et al. (2011) shows that rats previously treated with risperidone in the induction phase showed stronger reactivity to the avoidance-disruptive effect of olanzapine administered in the expression phase. Recently, a cross-sensitization from asenapine to olanzapine in both the conditioned avoidance response model (Figure 3) and the PCP-induced hyperlocomotion model (Figure 4) has also been observed (Qin et al., 2013).

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Figure 3.

Prior asenapine (ASE) treatment increased sensitivity to ASE re-exposure and olanzapine (OLZ) exposure in the avoidance response. (as) Number of avoidance responses in the ASE (0.10 mg/kg) challenge test; (b) OLZ (0.50 mg/kg) challenge test and (c) clozapine (CLZ, 2.50 mg/kg) challenge test is expressed as mean+standard error of the mean (SEM), *p<0.05, **p<0.01 relative to the vehicle (VEH) group; #p<0.05 relative to the ASE 0.05 group. Adapted from Qin R, Chen Y and Li M (2013) Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity. Neuropharmacology 75C: 356–364 with permission from Elsevier.

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Figure 4.

Prior asenapine (ASE) treatment increased the inhibition of PCP-induced hyperlocomotion upon asenapine re-exposure and on olanzapine (OLZ) and clozapine (CLZ) treatment in adult rats. (a) Locomotor activity was measured for 60 min after vehicle (for the vehicle (VEH)+VEH-1 group) or PCP (3.20 mg/kg, sc, for the other five groups) injection and expressed as mean+standard error of the mean (SEM) for each group. ASE (0.10 mg/kg, sc) was injected 30 min before the vehicle or PCP injection. (b) Locomotor activity was measured for 60 min after vehicle or PCP injection and expressed as mean+SEM for each group. OLZ (0.50 mg/kg, sc) was injected 30 min before the vehicle or PCP injection. (c) Locomotor activity was measured for 60 min after vehicle or PCP injection and expressed as mean+SEM for each group. CLZ (2.50 mg/kg, sc) was injected 30 min before the vehicle or PCP injection. (n=8/group). Both the VEH+VEH-1 and VEH+VEH-2 groups were repeatedly injected with 0.9% saline for five consecutive days in the induction phase. The only difference was that on the challenge test days, the VEH+VEH-1 group was injected with ASE/OLZ/CLZ followed by another saline injection, whereas the VEH+VEH-2 group was injected with ASE/OLZ/CLZ followed by a PCP injection. **p⩽0.001 relative to VEH+VEH-1 group; #p<0.05, ##p≤0.001 relative to VEH+VEH-2; &p<0.05, &&p⩽0.004 relative to VEH+PCP; $p<0.05, $$p⩽0.009 relative to ASE 0.20+PCP group. Adapted from Qin R, Chen Y and Li M (2013) Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity. Neuropharmacology 75C: 356–364 with permission from Elsevier.

Factors that influence antipsychotic sensitization and tolerance

It is common knowledge that both pharmacological factors (e.g. dose, schedule, and route of drug administration, presence of other drugs, etc.) and nonpharmacological factors (e.g. environmental stimuli, selected behavioral responses, passage of time, etc.) affect the development of behavioral sensitization and tolerance induced by psychoactive drugs (Emmett-Oglesby and Goudi, 1989). Behavioral sensitization and tolerance induced by antipsychotic drugs are no exceptions. This section selectively reviews relevant reports, illustrating the principles of how these two classes of factors exert their impacts on the induction and expression of antipsychotic sensitization and tolerance.

Developmental impacts: Altered drug sensitivity due to adolescent drug exposure

Antipsychotic treatment in children and adolescents has increased dramatically in recent decades (Kalverdijk et al., 2008; Olfson et al., 2006; Rani et al., 2008). Epidemiological surveys conducted in many countries (e.g. UK, US, Germany, Netherlands) indicate a two- to six-fold increase in the number of prescribed antipsychotics for young patients (⩽20 years) between the 1990s and the mid-2000s (Kalverdijk et al., 2008; Olfson et al., 2006; Rani et al., 2008). More than 90% of the children and adolescents who are treated with antipsychotic medications are on atypical drugs (e.g. risperidone, olanzapine, and aripiprazole) for the management of disruptive behavior disorders (37.8%), mood disorders (31.8%), pervasive developmental disorders, or mental retardation (17.3%) and psychotic disorders (14.2%) (Olfson et al., 2006). Clinical research on antipsychotic treatment in children and adolescents primarily focuses on the efficacy, tolerability, and side effect profiles of individual drugs. There is a general lack of research on the long-term consequences of adolescent antipsychotic treatment on the brain and the behavioral development of patients.

Preclinical studies strongly suggest that antipsychotic exposure in adolescence could alter brain and behavioral functions. For example, animal receptor binding studies show that antipsychotic exposure during adolescence increases or decreases various neuroreceptors, including dopamine D₁, D₂, and D₄ receptors (Moran-Gates et al., 2006; Vinish et al., 2013), serotonin 5-HT_1A and 5-HT_2A receptors (Choi et al., 2010), and ionotropic NMDA and AMPA glutamatergic receptors (Choi et al., 2009). Behavioral studies also suggest that early adolescent antipsychotic exposure enhances animals’ sensitivity to reward stimuli (Vinish et al., 2013), impairs their working memory, delays the extinction process of fear memory in adulthood (Milstein et al., 2013), and prevents the development of various psychosis-like behaviors (e.g. prepulse inhibition (PPI) deficit, latent inhibition deficit, etc.) induced by maternal immune activation (PolyI:C injection during pregnancy), while impairing certain behavioral functions of normal animals (Meyer et al., 2010; Piontkewitz et al., 2009, 2011, 2012).

In addition to the effects on basic brain and behavioral functions, adolescent antipsychotic exposure can also alter later antipsychotic responses in adulthood. Since 2012, we have conducted a series of experiments and delineated the extent to which antipsychotic exposure during adolescence affects ‘exposure-dependent’ alterations. Similar to what has been reported in adult animal studies, two patterns of alterations: sensitization and tolerance are also identified. The first study used the conditioned avoidance response model and addressed two important issues: first, whether olanzapine sensitization and clozapine tolerance can be induced in adolescent rats; second, the extent to which olanzapine sensitization and clozapine tolerance induced in adolescence persist into adulthood (Qiao et al., 2013). The basic paradigm is similar to that depicted in Figure 1. Male adolescent rats (~postnatal days (P) 43–47) were first treated with olanzapine or clozapine daily for five consecutive days and then challenged either in adolescence (~P 50) or after they matured into adults (~P 76 and 92). Olanzapine sensitization and clozapine tolerance were found in the behavioral measures of antipsychotic activity (e.g. avoidance response and intertrial crossing), but not in the measure of fear (e.g. CS-induced 22 kHz ultrasonic vocalizations (USVs)) (Mead et al., 2008; Sun et al., 2010). These findings suggest that antipsychotic treatment during adolescence can induce a long-term specific alteration in antipsychotic effect that persists into adulthood despite the brain maturation. Both olanzapine sensitization and clozapine tolerance effects are dose-dependent, specific to the antipsychotic effect (e.g. anti-avoidance), but not to the anxiolytic effect (e.g. a decreasing effect on 22-kHz USVs). These results also support the idea that the different behavioral effects of an antipsychotic drug undergo different time courses of change after repeated administration (Stewart and Badiani, 1993).

Following this initial study, a series of studies have been conducted on other antipsychotic drugs. Risperidone, asenapine, and haloperidol are all found to cause a sensitization effect that persists into adulthood in a similar fashion as olanzapine in the conditioned avoidance response model (Gao and Li, 2014; Qiao et al., 2014b; Shu et al., 2014a) (see Figure 5). In addition, adolescent risperidone treatment could even alter adulthood responsiveness to olanzapine (a cross-sensitization effect) and clozapine (Qiao et al., 2014b). Specifically, evidence indicates that adolescent risperidone treatment essentially enhances olanzapine sensitization and clozapine tolerance. These long-lasting changes are likely mediated by drug-induced neuroplastic changes and could have significant clinical implications because risperidone has been one of the most prescribed antipsychotic agents for children and adolescents (Patel et al., 2005) and drug switching is quite common in people with schizophrenia during the course of optimizing therapeutic regimens for individual patients (Rosenheck et al., 2009). These findings suggest that the past history of a patient’s experience with a given drug may impact his/her later response to a new drug. Thus, clinicians working with adult patients who have been treated with one drug (e.g. risperidone) but wish to switch to another drug (e.g. olanzapine or clozapine) may need to consider possible changes in antipsychotic efficacy and monitor patients’ symptom response to the new drug during this switching process.

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Figure 5.

Repeated asenapine (ASE) treatment increased the suppression of avoidance response in adolescent rats (postnatal days, P 43–48) (a) and increased sensitivity to ASE re-exposure in the challenge test in adulthood (P ~76) (b). Number of avoidance responses made by the rats from the ASE (0.05 mg/kg), ASE (0.10 mg/kg), ASE (0.20 mg/kg) and vehicle groups on the last training (pre-drug) day, during the five drug test days and on the challenge test day are expressed as mean+standard error of the mean (SEM). **p<0.004, three ASE groups relative to the VEH group; #p<0.05, ASE 0.10 and ASE 0.20 groups relative to the ASE 0.05 group, respectively. Adapted from Shu Q, Qin R, Chen Y, et al. (2014b) Asenapine sensitization from adolescence to adulthood and its potential molecular basis. Behav Brain Res 273: 166–176 with permission from Elsevier.

In order to validate the generality of adolescent antipsychotic sensitization and clozapine tolerance effects, it is necessary to employ a similar test paradigm used in one test (e.g., the conditioned avoidance response model) and apply it in another (e.g. PCP-induced hyperlocomotion model). Shu et al. (2014a) did just that (see Figure 6). This study showed that during adolescence, repeated olanzapine or clozapine treatment produced a persistent inhibition of PCP-induced hyperlocomotion across the five test days. In the challenge test during adolescence, rats previously treated with olanzapine did not show a significantly stronger inhibition of PCP-induced hyperlocomotion than those previously treated with vehicle. In contrast, those previously treated with clozapine showed a weaker inhibition than the vehicle controls. When assessed in adulthood, the enhanced sensitivity to olanzapine and the decreased sensitivity to clozapine were detected on ~P 76, even on ~P 91 in the case of olanzapine. These findings suggest that adolescent olanzapine or clozapine exposure can induce long-term alterations in antipsychotic response that persist into adulthood. A subsequent study demonstrated that repeated risperidone treatment in adolescence could also cause a sensitization effect in this model of antipsychotic activity (Qiao et al., 2014a).

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Figure 6.

Olanzapine (OLZ) sensitization from adolescence to adulthood. Locomotor activity was measured during the 60-minute test period after daily PCP injection throughout the five test days (left) and during the OLZ challenge test on postnatal day (P) 76 (right). OLZ at 1.0 and 2.0 mg/kg induced a sensitization effect in adulthood. Adapted from Shu Q, Hu G and Li M (2014a) Adult response to olanzapine or clozapine treatment is altered by adolescent antipsychotic exposure: A preclinical test in the phencyclidine hyperlocomotion model. J Psychopharmacol 28: 363–375.

Much of our adolescent antipsychotic sensitization and tolerance work has relied on a daily intermittent drug injection schedule for a short period of time (e.g. five days). How these long-term effects are modulated by treatment schedule has never been examined. In a recent study (Gao and Li, 2014), we explored how haloperidol sensitization induced throughout adolescence and tested in adulthood was differentially impacted by these two dosing regimens in the conditioned avoidance response test (Figure 7). Adolescent rats were treated with haloperidol continuously (via osmotic minipump) or intermittently (via daily injection) from P 44 to 71. Haloperidol sensitization was assessed in a challenge test in adulthood (>P 80) in which all rats were injected with haloperidol. Interestingly, only the intermittent dosing group showed a robust sensitization effect. This finding suggests that adolescent haloperidol sensitization is a schedule-specific phenomenon, much like what we observe in other behavioral effects of antipsychotic drugs (Samaha et al., 2008; Turrone et al., 2005). It is more likely to be seen under an intermittent dosing regimen than under a continuous dosing one.

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Figure 7.

Effects of chronic continuous versus intermittent haloperidol (HAL) treatment on conditioned avoidance responding over time. (a) Number of avoidance responses made by the rats treated with HAL-0.25 CONT (0.25 mg/kg/day via minipump, n=14), HAL-0.05 INT (0.05 mg/kg/injection/day sc, n=14) or vehicle (VEH, n=13) on the predrug (0) day, and drug test days. ***p<0.001 for comparisons between HAL-(0.05 INT and 0.25 CONT) and vehicle (VEH); ###p<0.001, ##p<0.01, #p<0.05 for comparisons between HAL-0.05 INT and HAL-0.25 CONT on each test day. (b) Number of avoidance responses made by the three groups of rats in the HAL 0.05 mg/kg challenge tests. After retraining, all groups were injected with HAL 0.05 mg/kg (sc) 11 days after the last HAL treatment. Avoidance tests were conducted 60 min later. All data are expressed as mean+standard error of the mean (SEM). **p<0.01 for comparison to the VEH group; ##p<0.01 for comparison to the HAL-0.05 INT group. Adapted from Gao J and Li M (2014) Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood. Prog Neuropsychopharmacol Biol Psychiatry 54: 67–75 with permission from Elsevier.

Recently, we showed that persistent aripiprazole sensitization from adolescence to adulthood is sex-dependent (unpublished observation). In both the induction phase and the expression phase, male rats always had significantly lower avoidance than the females under aripiprazole, indicating that male rats might be more sensitive to aripiprazole treatment. This result suggests that antipsychotic sensitization might vary between sexes and clearly has a significant clinical implication if replicated.

As discussed at the beginning of this section, adolescent antipsychotic treatment is known to exert long-term impacts of basic behavioral and brain functions. However, no studies have examined whether adolescent antipsychotic treatment would affect social functioning in adulthood, one of seven primary cognitive domains that are affected in schizophrenia (Floresco et al., 2005; Green et al., 2004,). Gao and Li (2014) examined how intermittent and continuous haloperidol treatment may potentially impact social interaction and social memory using a paradigm that we validated in amphetamine and phencyclidine-based animal models of schizophrenia (Li et al., 2012). The social memory of rats was evidenced by the findings that a subject rat decreased its time investigating the same testing partner after a waiting period (~10 min) and increased its time on investigation if a novel partner was introduced (Akers et al., 2006; Holloway and Thor, 1988; Prediger et al., 2004,). Our results show that adolescent haloperidol treatment (continuous and intermittent) did not affect social behavior and social memory, as rats from the two haloperidol groups and the vehicle group exhibited a similar level of social interaction and showed a similar level of sensitivity to the change of social stimuli. This finding suggests that adolescent haloperidol treatment under both regimens did not fundamentally damage social functioning. Thus, the clinical significance of haloperidol sensitization needs to be further examined.

Collectively, these important findings firmly establish that antipsychotic treatment in adolescence can induce a long-term change in drug responsiveness that persists into adulthood. This altered sensitivity appears to be sex- and regimen-specific. Because antipsychotic drugs are being increasingly used in children and adolescents in the past two decades, findings from this study are important for understanding the impacts of adolescent antipsychotic treatment on the brain and behavioral developments. Furthermore, although we have demonstrated that environmental stimuli and behavioral response associated with drug treatment have a profound impact on the induction and expression of antipsychotic sensitization and tolerance in adult animals (Feng et al., 2013; Sun et al., 2014; Zhang and Li, 2012), there is no study that has examined how such factors could affect adolescent antipsychotic sensitization and tolerance. Given their potential effects on brain development, if we can identify the clinical and experimental conditions that modulate adolescent antipsychotic sensitization and tolerance, we could then better use them to our advantages. This work also has implications for clinical practice involving adolescent antipsychotic treatments in terms of drug choice, drug dose, and schedule, and treatment setting.

Neurobiological mechanisms

Although behavioral sensitization and tolerance induced by antipsychotic drugs are well established, the molecular mechanisms (e.g. receptor, intracellular signaling molecules) and neural basis of these effects are less clear. Given the fact that all antipsychotic drugs have immediate actions on dopamine D₂ and 5-HT_2A receptors (Meltzer et al., 1989; Meltzer et al., 2003; Miyamoto et al., 2005), and repeated antipsychotic treatment induces long-term changes in these receptors (Tarazi et al., 2001), one naturally suspects that changes in these receptors may account for the behavioral sensitization and tolerance induced by antipsychotic drugs. As the following results may show, antipsychotic-induced changes in D₂ and 5-HT_2A receptors in the various limbic areas are indeed in part involved in the mediation of the induction and/or expression of antipsychotic sensitization or tolerance. It should be noted that because many antipsychotics also have various degrees of affinity for a number of other neuronal receptors, including α-adrenergic, histamine H₁, serotonin 5-HT_1A, 5-HT₆ and 5-HT₇ receptors, and muscarinic receptors, and this multi-receptor action is likely to affect their efficacy and side effect profile (Lieberman et al., 2008), the magnitude and persistence of antipsychotic sensitization and tolerance might also be, to some extent, modulated by these receptor-binding affinities. Unfortunately, there is little research on the involvement of receptors other than D₂ and 5-HT_2A in antipsychotic sensitization and tolerance. Therefore, on the receptor mechanisms, we will have to limit ourselves to these two receptors.

Summary and future research

It is well documented now that antipsychotic drugs are exogenous stimuli that impact the brain and cause long-term behavioral changes and associated neuroadaptations. Behaviorally, antipsychotic-induced changes reflect an increase (sensitization) or decrease (tolerance) in drug sensitivity and environmental cues and behavioral response associated with drug treatment have a profound impact on the induction and expression of antipsychotic sensitization and tolerance. Neurochemically, dopamine D₂ and serotonin 5-HT_2A receptors play a role in these two behavioral effects of antipsychotic treatment. Neuroanatomically, the mPFC-related neural circuitry is critically involved in the clozapine tolerance, while other regions (e.g. NAs, VTA, and CeA) may be involved in the mediation of antipsychotic sensitization.

The present paper reviews some of the important evidence in the literature, focusing on the drug-induced changes in antipsychotic response. It is fair to say that although the research community of antipsychotic drugs is relatively large and highly active, this particular field (i.e. research on antipsychotic sensitization and tolerance) is rather small, and much of the work comes from a limited number of laboratories and uses a limited number of animal models (e.g. conditioned avoidance, PCP-induced hyperlocomotion, etc.). Therefore, it is imperative for future research to raise the profile of this area by focusing several areas, as outlined below.

One major area of research is to determine the clinical relevance of antipsychotic sensitization and tolerance. Are they clinically relevant for the explanation of the clinical effects (both therapeutic and side effects) of antipsychotic treatment? What clinical effect could be explained by sensitization and what could be explained by tolerance? What pharmacological features account for the differences between sensitization and tolerance? Why does clozapine primarily cause a tolerance in several behavioral tests of antipsychotic activity, while others induce a sensitization? Could this difference explain the superior treatment effect of clozapine? etc. What clinical phenomena are associated with clozapine tolerance? Clinician scientists could help answer these questions by looking into these two mechanisms as explanatory tools. At this time, it is fair to say that preclinical findings on antipsychotic sensitization and tolerance have not made a good connection with clinical research. Thus basic psychopharmacologists also need to understand clinical phenomena better.

As mentioned, antipsychotic sensitization and tolerance have not been systematically studied in a preclinical disease model of schizophrenia. All the published work so far has been done in otherwise healthy male rats. Therefore, the face validity is low as only humans with severe mental disorders such as schizophrenia receive antipsychotic therapy. Animal work also suggests that antipsychotic treatment has differential effects on “diseased” rodents and normal controls (Meyer et al., 2010). Thus, one important future focus for basic scientists is to examine antipsychotic sensitization and tolerance in animal models of schizophrenia. Resolving this issue could also help determine the clinical significance of antipsychotic sensitization and tolerance.

To date, limited research is available on the effects of adolescent antipsychotic exposure on basic psychological functions such as attention, novelty-seeking, emotion, and learning and memory (Milstein et al., 2013; Vinish et al., 2013). How antipsychotic sensitization and tolerance contribute to these effects has never been explored. Furthermore, whether functional changes in D₂ and 5-HT_2A receptor expressions induced by adolescent antipsychotic treatment are related to drug-induced behavioral effects has not been examined. Future research should fill these knowledge gaps by connecting what we know about the basic behavioral effects of adolescent antipsychotic treatment with the treatment’s intrinsic property of altering drug sensitivity. This research will significantly enhance our understanding of the positive and negative impacts of adolescent antipsychotic treatment on drug response, behavioral functions, and brain functions.

Another important research area is to identify the neural mechanisms of antipsychotic sensitization and tolerance. Because antipsychotic drugs have a profound impact on a variety of brain signaling molecules involved in a variety of important yet different brain functions (e.g. synaptic neurotransmission, neuroendocrine regulation, oxidative stress, adult neurogenesis etc.) (Chou et al., 2015; Seeman, 2002; Stojkovic et al., 2012), and even though we are certain that the sensitization and tolerance induced by these drugs must reflect the consequences of drug-induced neuroplastic changes, we do not fully understand the exact and critical mechanisms underlying the long-term sensitization and tolerance effects. There is not much research that has made an effort to connect drug-induced brain changes at the molecular/system level to the sensitization and tolerance at the behavioral level. This line of inquiry should be one of the focuses of future antipsychotic research. One related area of research is to investigate the neurobiological mechanism underlying the environmental control of the induction and expression of antipsychotic sensitization and tolerance. This work will help us gain better understanding of the neurobiological mechanisms underlying sensitization and tolerance effects.

Also, clinical evidence suggests that women react more favorably to antipsychotic therapy than men (Szymanski et al., 1995), and preclinical evidence also suggests that sex of animals is an important factor in the modulation of antipsychotic response, with females tending to have increased sensitivity to antipsychotic treatment due to lower D₂ affinity compared to males (Pohjalainen et al., 1998). Our recent study also indicates that the magnitude of aripiprazole sensitization differs between male and female rats. With NIH’s increased emphasis on sex as a biological variable in the design and analysis of NIH-funded research involving animals, determining antipsychotic sensitization and its impact on basic behavioral and brain functions in both male and female animals becomes especially urgent. Unfortunately, all published antipsychotic sensitization studies so far used only male animals. On the dosing regimens, much of this work only used a daily intermittent drug injection schedule for a short period of time (e.g. five days) and most only tested male normal rats, while both clinical and preclinical evidence suggests that females tend to have delayed onset of psychopathology of schizophrenia (Han et al., 2012; Piontkewitz et al., 2012) and increased sensitivity to antipsychotic treatment due to lower D₂ affinity compared to males (Pohjalainen et al., 1998). It is thus important to examine sex differences in antipsychotic sensitization and tolerance and use a variety of different dosing regiments, such as continuous treatment via osmatic minipumps or drinking water or prolonged treatment for months.