Psychosis and Fever Revisited

During the development of DSM-5, when it was still DSM-V, Fischer and Carpenter (Fischer & Carpenter, 2009) were perplexed by the continued reliance on reality distortion in the schizophrenia diagnosis: “the brain generates hallucinations and delusions in so many conditions that it is difficult to understand how [they] have maintained primacy …. Psychotic experience is to the diagnosis of mental illness as fever is to the diagnosis of infection – important, but non-decisive …” (p. 2082). Two great Minnesota trained psychologists favored a similar form of this argument. One was Paul Meehl (1990): “… current psychiatric nosology … is more like [a] list of ‘kinds of fever,’ demarcated by … arbitrary … clumps of the descriptive syndrome, which often include distinguishing features that are quite irrelevant either in theoretical causal understanding or in therapeutic indications” (pp. 24–25). The other was Scott Lilienfeld when discussing an experiential approach to psychiatric diagnosis: “… in the early twentieth century, physicians diagnosed dozens of different fevers … and distinguished them … [by] co-occurring signs and symptoms …. Today, physicians recognize that fever is a nonspecific indicator of a plethora of pathologies …” (Lilienfeld & Treadway, 2016).

Is the psychosis-fever analogy appropriate? Should we care that reality distortions (hallucination and delusions) occur across the range of human experience, including among persons with a schizophrenia diagnosis (Loch, 2019)? After all, differential diagnosis of a patient presenting with reality distortion is not completely determined by those symptoms. Dr. Will Carpenter repeatedly, and usefully, pinpoints the fundamental event. It happened 40 years ago. After describing the deed, well known to many, but perhaps not appreciated by some, I suggest that clinical neuroscience investigation of schizophrenia specifically, and psychosis generally, consider two modifications to its program.

The foundational forebears of the schizophrenia construct are Eugen Bleuler, who coined and defined ‘schizophrenia’, and Emil Kraepelin, whose ‘dementia praecox’ was an earlier diagnosis to which Bleuler’s conceptualization was a response. Both Bleuler and Kraepelin emphasized disintegration of the personality, lack of integration of thoughts, feelings, and actions, and volitional disturbances as this condition’s core (Kendler, 2020; Moskowitz & Heim, 2011). Kraepelin also emphasized a “peculiar state of mental impairment” (Kendler, 2020) and “weakening of the wellsprings of volition,” the latter concept Carpenter and Buchanan (2017) link to contemporary understanding of negative symptoms in psychosis. Kendler (Kendler, 2020, 2021) discovered that Kraepelin considered particularly bizarre reality distortions to be prominent clinical features of dementia praecox but did not believe permanent delusional systems were characteristic of this most serious of psychiatric conditions. Reality distortions are not topping the list of foundational core features.

The gateway to a psychosis diagnosis is the “Criterion A” part of DSM’s schizophrenia definition. Published in 1980, DSM-III lists six elements in Criterion A, of which one element must be met to qualify: the first five are types of reality distortion, the sixth is evidence of thought disturbance. To meet this last element, a patient must also have (a) affective disturbance or (b) any type of reality disturbance or (c) disorganized behavior. Kendler (Kendler, 2016) reports that “thought disorder and emotional blunting,” delusions, especially “bizarre, fantastic” types, and auditory hallucinations were prominent in early- to mid-1990s conceptualizations of schizophrenia. DSM-III effectively trivialized thought disorder and emotional blunting, two components of apparently most schizophrenia theorists’ foundational core, while still including those features in the definition. DSM-III transformed schizophrenia’s essence from affect, self, and volition disturbances to reality distortion. This was a new clinical theory.

In 1994, DSM-IV superficially soothed the reality distortion concern. Criterion A in DSM-IV is met by a patient showing any two of the following five features: delusions, hallucinations, disorganized speech, grossly disorganized behavior, or negative symptoms. Simultaneously, DSM-IV doubled down on reality distortion by requiring only one example of a Schneiderian first rank-type symptom, particularly bizarre forms of reality distortion, to meet Criterion A. This was done despite knowing, even before DSM-III (Carpenter & Strauss, 2019; Mellor, 1982; Strauss & Carpenter, 1978), that these reality distortions are of ambiguous diagnostic and clinical utility. Reality distortion maintained substantial heft for diagnosing schizophrenia, but now the definition was clinically bipartite (reality distortion alone or no reality distortion at all meets Criterion A). This was a modification of a new clinical theory.

Hallucinations and delusions are frequent symptomatic manifestations in schizophrenia. This is indisputable. The issue is whether reality distortions deserve primacy over the historical foundational core. Dr. Tom Insel, NIMH Director from 2002–2015, in his “Rethinking Schizophrenia” (2010), addresses this issue through a key observation. Reality distortion is the brain signaling dysregulation of some unknown mechanism. For idiopathic psychosis, this mechanism probably has been stressed for a considerable chunk of a person’s neurodevelopmental trajectory. Reality distortions are the product of a longitudinal disease process that affected this unknown mechanism.

Analogies can be logically tricky, but in this case at least worthy of contemplation. Pyrexia indicates disease but is not the disease itself. Antipyretics are used for palliative care while searching for the primary pathology. Richard Wyatt, in Schizophrenia Research’s inaugural issue, concluded:

neuroleptic medications have an equipotent clinical effect on psychotic symptoms in affective disorders as well as in schizophrenia. … One might argue that schizophrenia and affective disorders are actually the same disease. … we are led to conclude that even though neuroleptics may alter psychosis by a common process, not all psychoses are produced by the same etiologic mechanism.

(Wyatt et al., 1988, p. 14)

In other words, antipsychotics are palliative care for psychosis, they are not addressing the disease, only the mechanism(s) disrupted because of the disease process(es).

Clinical evaluation of a person presenting with pyrexia has advantages over the psychosis workup (Clementz, 2020): knowledge of the mechanism generating fever independent of the disease (pyrogens and their detection by thermoregulatory neurons in the anterior hypothalamus), a measuring device independent of patient report and clinical signs (thermometer), and laboratory tests to identify the underlying disease for which treatment is then targeted. Nevertheless, why is there no known mechanism for reality distortions if they are the psychiatric equivalent of pyrexia? Is there, or has there ever been, a research program capable of addressing this question? One thing is certain. If the psychosis-fever analogy is appropriate, we have a problem.

My first suggestion is to intensively search for a reality distortion mechanism independent of any specific diagnosis. Certain events (e.g., drugs, brain trauma, NMDA receptor encephalopathy) yield reality distortion. That does not mean we understand the mechanism(s) by which the brain generates such symptoms. Is there one mechanism for all reality distortions with different psychotogens causing its disruption? Distinct mechanisms for hallucinations and delusions, either as a group (e.g., all delusions) or by individual symptom type (e.g., first rank symptoms versus all others)? This mission could yield a measuring device for psychosis, independent of clinical examination, and allow for separating reality distortion and disease process(es) variances. This would be a game changer.

Why are there no laboratory tests for schizophrenia? The overwhelming majority of psychosis studies use DSM-type diagnoses as targets. Perhaps they do not capture neurobiological reality (Casey et al., 2013; Hyman, 2007; Sullivan et al., 2018). We find in B-SNIP studies (Clementz et al., 2021) that DSM-IV-TR psychosis diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis are at best marginally distinguishable on multiple measures, including basic sensory processing, motor performance, inhibition, target detection, memory functions, executive control, and brain structure and function (Sprooten et al., 2017; Wexler, 1992). We developed an alternative for identifying possibly meaningful psychosis subgroups, called Biotypes, that replicate, cross-validate, show promising construct validity, and yield treatment targets not derivable from DSM diagnoses (Clementz et al., 2021, 2020). If neurobiology matters for improving patient care, an open question for idiopathic psychosis, such an approach may prove useful.

Despite this promising foundation, B-SNIP psychosis Biotypes are quantitatively defined and dependent on inputs to numerical taxonomy. They are the outcome of Minnesota style dustbowl empiricism. Curiously though, the clinical features maximally differentiating Biotypes are poor social and occupational functioning, difficulty in abstract thinking, conceptual disorganization, blunted affect, lack of spontaneity, and poor attention (Clementz et al., 2020). Maybe our foundational forebears knew something about capturing neurobiological homology, maybe this is just a coincidence. But “top down” (committee consensus) and “bottom up” (biomarker homology) approaches to creating psychosis subgroups yield remarkably different clinical definitions. One has its roots in the shift of schizophrenia to reality distortion, the other appears at least superficially consistent with the pre-DSM-III foundational core.

My second suggestion is that we abandon a purely top-down approach to clinical neuroscience investigation of idiopathic psychosis. No more studies of DSM-type schizophrenia as the sole target. Psychosis research programs must work with multiple targets at multiple levels of analysis simultaneously (Wilson, 1998).

DSM-5 made significant improvements in conceptualizing idiopathic psychosis, not surprising since Will Carpenter was involved in the deliberations (Carpenter, 2013). Is the top-down approach to psychosis subgrouping primed for more extensive modification? The post-1980 clinical theories of schizophrenia, dramatically modified from the foundational core, lack strong support in facts. The psychosis-fever analogy helps place this state-of-affairs in context. We know for sure there is idiopathic psychosis, and that neurobiological variance in this overarching domain can be parsed. We don’t know the best approach or the best probes, but we know interesting treatment targets can be derived. We know antipsychotic medications offer important and palliative, sometimes life-changing treatments for persons with psychosis. But those medications are prescribed based on symptomatic presentation, not psychosis diagnosis. Given what we know, how long does the contemporary theory of schizophrenia survive (Guloksuz & van Os, 2021)? I can hardly wait for DSM-5.1.