Subjective tolerability of antipsychotic medications and the emerging science of subjective tolerability disorders

Subjective tolerability refers to how the person feels on medications. Tolerability in general, and in clinical trials of new antipsychotics in particular, has mostly referred to traditional side effects and safety. Interestingly, ‘subjective tolerability’ is missing as a term or a concept from the standard textbooks of pharmacology, medicine and psychiatry. It is clear that how a person feels on medications determines to a large extent if the person will continue to take the medications and eventually impacts on outcome of treatment itself. Such a simple proposition has frequently eluded researchers and clinicians. Clinicians were baffled by the frequent observation that a number of their patients suffering from schizophrenia treated with antipsychotics quickly develop a dislike for their medications, sometimes after only a few doses. For researchers investigating subjective constructs, such as subjective tolerability to medications, it proved to be difficult territory owing to the lack of reliable methodology to measure and quantify such responses [1]. At a time when the field had been moving towards objective scientific inquiry, subjective constructs were ignored as being ‘soft science’. Additionally, there has been lingering doubt regarding the reliability of patients with schizophrenia and doubts about their ability to consistently express their inner feelings. The paradox in such a position has been the reliance and acceptance in making a psychiatric diagnosis based on patient’s reports about their delusional and hallucinatory experiences, which are strictly subjective and not objectively verifiable, yet their reports regarding how they feel on medications has been suspect and frequently ignored.

Genesis of the construct of subjective tolerability to antipsychotics in schizophrenia

Soon after the introduction of the first antipsychotic, chlorpromazine, in the early 1950s, patients frequently complained of an altered and unpleasant subjective state: like a zombie, feeling awful, lazy, feeling dull or fuzzy [1,2]. Not surprisingly patients ended up discontinuing their medications or at least not taking them regularly [3–5]. Such phenomena received different labels in the early literature: behavioral toxicity, neuroleptic induced Anhedonia, akinetic depression, neuroleptic dysphoria and, in recent years, we introduced the label commonly used at present: negative subjective responses [6]. Although clinical significance of such phenomena was clear and recognized by clinicians, it was mostly ignored by researchers. In order to make the area accessible for research, there has been an urgent need to objectify the phenomenon of subjective responses by the development of conceptual models and measuring tools with sound psychometric properties, as well as demonstrating the reliability of the majority of psychiatric patients to consistently report their feelings. The earliest conceptual model introduced was a modification of an already existing model of drug response following the neurobiological pathway between ingesting an antipsychotic medication and the eventual behavioral and psychological responses by adding a mediating step before the eventual behavioral response: the subjective interpretation of physiological changes induced by drug effects [7,8].

Such individual interpretation of the internal physiological changes can mediate the eventual behavioral and psychological responses. A number of scales have been developed, ushered in by the development of the Drug Attitude Inventory (DAI), which still continues, since introduced in the 1970s, to be the standard measure for subjective responses on antipsychotics [4,9]. Other scales followed based on the DAI, such as Rating of Medication Influences (ROMI) [10], Subjective Wellbeing on Neuroleptic Medications (SWN) [11] and Personal Evaluation of Transitions in Treatment (PETiT) [12]. With the availability of reliable measuring tools, several studies demonstrated the reliability and consistency of the majority of psychiatric patients to be able to express and quantify their inner feelings [9,13–16]. With such methodological advancement, the past three decades has witnessed an expanded clinical and research interest in exploring the subjective world of our patients. Numerous clinical studies have confirmed and expanded on the concept, its relevance in clinical management and impact on important outcomes: medication adherence behavior, clinical outcome and quality of life [3,7–9,17–20]. The recent enhanced interest in patient-reported outcomes has given further impetus to the importance of subjective constructs, such as subjective tolerability to medications, satisfaction with medication and particularly with the recent acceptance of such patient-reported outcomes by regulatory agencies such as the US FDA and European community for use in clinical trials of new medications [101].

Neurobiology of subjective tolerability to antipsychotic medications

Neuroleptic dysphoria and negative subjective responses has long been suspected all along to be related to alterations in central dopamine functioning [21]. The phenomenon has been reported with dopamine blocking agents, such as antipsychotics, as well as in conditions associated with low dopamine function, such as in Parkinson’s disease [22,23]. However, there was no direct proof until the recent advent of neuroimaging and advances in the field of receptor quantification that has allowed direct visualization of synaptic dynamics and its correlation with clinical symptoms [24,25]. Our α-para-aminotyrosine (AMPT) dopamine depletion SPECT study was one of the earliest to demonstrate a direct link: an inverse relationship between dysphoric negative subjective responses and dopamine binding ratio in the nucleus accumbens and the nigrostriatal area in medication-free persons of schizophrenia [26,27]. In other words, those patients who have lower dopamine functioning are the ones who are vulnerable for dysphoric responses when further given potent dopamine blocking antipsychotics. This observation has also clarified why not all persons with schizophrenia develop negative subjective responses on antipsychotic medications, confirming early observations that not all persons with schizophrenia have high dopamine D₂ functioning [28]. Observing the cascade of events of behavioral effects following dopamine depletion, it became clear that alterations in subjective feelings are the earliest reported event observed in the first few hours to be followed by further affective changes, followed by motor and cognitive changes [27]. In essence, negative subjective tolerability proved to be not just an alteration in the affective state but is more complex and includes cognitive, motor, extrapyramidal and motivational changes. Our early study has already been replicated and expanded by several neuroimaging PET investigations [29,30].

As subjective negative tolerability has been demonstrated to be the earliest of the cascade of behavioral events that follows ingestion of antipsychotic medications, negative subjective tolerability can serve as an early clinical marker of the patient who likely will experience side effects and probably will not respond well to the particular medication.

In summary, it is clear that the new understanding of the neurobiology of negative subjective tolerability to antipsychotics is grounded in the demonstration of alterations in the functioning of the dopamine D₂ receptors and the dynamic interaction between the state of the receptor, which relates to the illness itself, and the pharmacological properties of the medication.

Negative subjective tolerability & comorbid substance abuse

The frequent association of comorbid drug abuse in schizophrenia is well established [31]. In total, 47% of individuals with schizophrenia compared with 13.5% in the general population has or had evidence of drug abuse, as revealed by the epidemiological US catchment area survey in 1990 [32]. Individuals with schizophrenia are more likely to abuse hard drugs, such as amphetamines, cocaine and cannabis, and generally consume large amounts of stimulants, such as coffee, and smoke heavily. The potential links connecting schizophrenia and substance abuse include: genetic vulnerability, medication and side effects, negative and depressive symptoms, as well as psychosocial factors. One of the prevailing hypotheses advanced to explain the frequent association of schizophrenia and drug abuse has been the ‘self medication hypothesis’ [33]. According to such a hypothesis, persons with schizophrenia take to drug abuse as a direct consequence of dealing with aspects of their illness experience or to alleviate some of the side effects, such as extrapyramidal symptoms or negative subjective responses. In 1997, we proposed that neuroleptic dysphoria may be the missing link between schizophrenia and substance abuse based on our findings that those patients with schizophrenia who experienced neuroleptic dysphoria have a higher likelihood to develop comorbid drug abuse compared with nondysphoric patients (odds ratio: 4.08; χ² = 21.8; p < 0.0001) [34]. Obviously, an association is not a causal link. Furthermore, although the self-medication hypothesis is intuitively appropriate, it proved not capable of explaining the total varied picture of coaddiction [35]. Several studies reported that drug abuse behavior predated the emergence of psychotic symptoms. The notion that the use of illicit drugs alleviates symptoms is not totally accurate. Abusing stimulants such as amphetamines can trigger a psychotic experience, which is hardly pleasurable, yet after recovery, such persons return back to amphetamines abuse. The recent demonstration of elevated rates of substance use disorders in nonpsychotic siblings of individuals with schizophrenia added to the notion of possible common genetic vulnerability for schizophrenia and substance use [36].

Recent advances in neurobiology have strongly implicated dopamine in the development of addictive states as also in schizophrenia, particularly in that both conditions share the same neuronal circuitry that mediates motivational behavior, drug reward and reinforcement [37]. Dopamine activity in the nucleus accumbens has been implicated in the mechanism of reinforcement for almost all drugs of abuse [38]. Recent evidence suggests that hyperdopaminergic states, as proposed in schizophrenia, can disrupt the adaptive mechanism of the dopamine neurons in response to novel rewards [39]. A hyperdopaminergic state produced by dysfunctional cortical/hippocampal input to nucleus accumbens can lead to continuous neural representation of reward as a novel stimulus, a mechanism central to initiation and maintenance of addictive behavior. Furthermore, recent experimental studies demonstrated the role of antipsychotics in reinforcement of addictions with the demonstration that chronic haloperidol treatment in animals increased the reinforcing properties of cocaine through upregulation of postsynaptic dopamine receptor in response to chronic blockade [40]. Consistent with the hypothesis of addiction–psychosis–vulnerability model, preliminary data mostly from uncontrolled studies suggest that treatment with clozapine and other atypical antipsychotic (weak dopamine blockers) may be associated with a decrease in substance abuse in schizophrenia [41].

Unifying hypothesis for subjective tolerability, comorbid drug abuse & schizophrenia

Since dysphoric and negative subjective tolerability can be construed, on one hand, as negative reinforcement, while the use of a stimulant, such as cocaine, as a positive reinforcement in the same neuronal circuit, it is possible to contemplate a model where negative subjective tolerability on one hand and vulnerability to addiction on the other hand are probably the manifestations of the dopamine disregulation process in the hippocampal–cortical–accumbens as part of the schizophrenia illness process itself. The recent enhanced research efforts, particularly in the experimental field, have yielded valuable information in clarifying the role of different components related to the neurobiological vulnerabilities to schizophrenia and addictive states. The challenge now is how to connect the dots into a clear and coherent neurobiological network that provides the links between both conditions.

I believe that recent intensified neuroimaging studies, particularly in the field of receptor quantification, have opened a new research vista exploring the concept of subjective tolerability. Understanding the neurobiology of subjective tolerability in both its positive and negative aspects has broader implications, not only owing to its relevance to clinical management and its impact on outcome to medication therapy, but also in terms of new medication’s development and understanding the addictive liability of medications [35].

It is my belief that current psychoneurobiological advancement has ushered in an emerging new science: the science of subjective tolerability disorders [6,35].

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.