Schizophrenia's 'Positive', 'Negative' Terms Are Misleading

The distinction between positive and negative symptoms in schizophrenia was popularized in the 1980s with the Positive and Negative Symptom Scale, which is widely used in drug treatment studies. Unfortunately, the terms "positive" and "negative" are sufficiently vague in ordinary English that they obscure the scientific and clinical meanings they are meant to convey. Typically, a "positive" symptom is meant to refer to delusions or hallucinations — what we have termed psychosis. "Negative" symptoms refer to flat affect, avolition, apathy, and the overall absence of emotional life, as described by Kraepelin in dementia praecox.Nassir Ghaemi, MD, MPHDelusions and hallucinations are, by Kraepelin's original definition, chronic and constant in schizophrenia. They can only decrease or increase in intensity; they do not go away completely. If they do, the diagnosis is not schizophrenia, but schizoaffective illness, or perhaps a mood illness. Believing that schizophrenia can respond completely to treatment, with all hallucinations and delusions disappearing, is akin to claiming that memory symptoms in Alzheimer's dementia can return fully to normal in the natural course of the illness. By definition, the symptoms of the disease, once they begin, are chronic and worsening. Treatment can improve them but cannot return the illness to its pre-onset baseline. This is a key distinction Kraepelin drew between dementia praecox and manic-depressive illness: A return to a pre-illness baseline occurs naturally in the latter, but not in schizophrenia.All of this concerns delusions and hallucinations, the so-called positive symptoms. Treatment studies with dopamine blockers generally show improvement in these psychotic symptoms. Flatness of affect, avolition, and apathy, however, do not improve independently; they can improve somewhat when psychotic symptoms improve, but a direct effect of dopamine blockers on these emotional symptoms is not seen. Because both sets of symptoms are labeled "positive" and "negative," many clinicians and researchers draw the facile conclusion that dopamine blockers work for positive symptoms but not negative ones, as though the two were comparable categories.Psychotic symptoms, as noted, are always present in schizophrenia but fluctuate, becoming better or worse. Apathy, avolition, and flatness of affect, by contrast, do not fluctuate. Once present, they stay present, or may worsen, but do not naturally improve, unlike delusions and hallucinations.This difference in the natural course of illness suggests that the two sets of symptoms are quite different entities ontologically — they are not the same kind of thing. Biological research over recent decades supports this view: flatness of affect appears to reflect a different biological process than delusions and hallucinations. Some evidence suggests that flatness of affect, avolition, and apathy are the central features of schizophrenia, beginning neurodevelopmentally at a young age — even in childhood — and becoming increasingly expressed by the time of diagnosis, preceding the onset of delusions and hallucinations, which typically emerge in adolescence or early adulthood.The biology of flatness of affect and avolition may involve early excessive glutamate activity, leading to excitotoxicity and neuronal cell death in brain regions important for motivation and affect, particularly the frontal lobe — a process that unfolds long before the onset of delusions and hallucinations in young adulthood. The biology of delusions and hallucinations, by contrast, may involve overactivity of the dopamine system in other brain regions, unrelated to flatness of affect and avolition. Dopamine blockers act on the biology of the latter, but not on the biology of flat affect, apathy, and avolition — a process that involves different neurotransmitters and begins very early in life, well before the first psychotic episode that leads to a diagnosis of schizophrenia.Figure 1. The developmental course of the primary process (flatness of affect, avolition, apathy) vs the secondary symptoms (delusions, hallucinations) in schizophrenia.Table 1. Primary vs Secondary Symptoms in SchizophreniaFeaturePrimary Process (Flat Affect, Avolition, Apathy)Secondary Symptoms (Delusions, Hallucinations)Conventional label"Negative symptoms""Positive symptoms"CourseConstant once present; does not fluctuate; can only worsenChronic but fluctuating; can improve or worsenResponse to dopamine blockersNo direct improvementGenerally improvesOnsetNeurodevelopmental; begins in childhood, precedes psychosisEmerges in adolescence or early adulthood, marking diagnosisProposed biologyEarly excessive glutamate activity → excitotoxicity → neuronal loss, particularly in the frontal lobeOveractivity of the dopamine system in other brain regionsCentrality (Kraepelin's view)The core, defining feature of dementia praecoxOccurs in both schizophrenia and manic-depressive illness; not the differentiatorKraepelin's Original View It is worth noting that Kraepelin's own view was that flat affect, not delusions or hallucinations, is the core feature of dementia praecox. Put in today's vaguer terms, his view was that negative features, not positive symptoms, characterize schizophrenia. Delusions and hallucinations occur in both schizophrenia and manic-depressive illness; the difference between the two conditions was not the presence of psychosis, but the presence or absence of affective symptoms. In manic-depressive illness, affective symptoms are strongly, and obviously, present; in schizophrenia, they are essentially absent.Importantly, in schizophrenia there is not an abnormality of affect in the sense of its being different in kind, but an absence of it — an abnormality of non-presence. In manic-depressive illness, by contrast, the abnormality of affect involves its excessive presence. Using the word "negative" for the former and "positive" for the latter implies that the absence of affect and avolition in schizophrenia is a comparable kind of thing to delusions and hallucinations. But both phenomenologically and biologically, the absence of affect, avolition, and apathy in schizophrenia is a different thing from delusions and hallucinations. They are two orthogonal processes within the disease, with the absence of affect being both earlier in onset and more central to the disease process than delusions and hallucinations.Table 2. Schizophrenia vs Manic-Depressive Illness: The Role of AffectFeatureSchizophreniaManic-Depressive IllnessDelusions or hallucinationsPresentCan also be presentAffective symptomsEssentially absentStrongly, obviously presentNature of the abnormality of affectAbsence of affect (non-presence)Excessive presence of affectKraepelin's key differentiatorAbsence of affectPresence, indeed excess, of affectImplications for Treatment and Terminology The search for new antipsychotic medications that will improve so-called negative symptoms is, on this view, a fool's errand: the so-called negative symptoms are not symptoms, in the ordinary sense, that can be reversed, but rather part of a disease process that begins early and becomes unchangeable once it has progressed to the point of an eventual diagnosis of schizophrenia. The only way to treat so-called negative symptoms would be to prevent them, with a disease-modifying medication given to individuals at risk for schizophrenia early in life — in childhood or adolescence — before the first psychotic episode. This would be the conclusion to draw if this interpretation of the nature of so-called negative and positive symptoms is correct.The proposal here is that we abandon these phrases, which derive from a rating scale rather than from the nature of the disease process itself. Instead, in referring to schizophrenia, we should refer to two aspects of the disease: the primary disease process — flatness of affect, avolition, and apathy — and the secondary symptoms — delusions and hallucinations. Put more simply, we should ban the vague and misleading words "negative" and "positive" from our lexicon and simply refer to "flat affect/apathy" vs "delusions/hallucinations", or even more briefly, to "apathy" vs "psychosis."Nassir Ghaemi, MD, MPH, is founder of Psychiatry Letter and a lecturer on psychiatry at Harvard Medical School, Cambridge Health Alliance, in Boston. Ghaemi is also an employee at Bristol Myers Squibb. The views presented here are his own and do not necessarily reflect those of his employers.