Natural History of Schizophrenia PDF

Here is a structured Markdown conversion of the provided document. # Chapter 2 # Natural History * Diana O. Perkins, M.D., M.P.H. * Jeffrey A. Lieberman, M.D. Schizophrenia typically emerges in late adolescence to early adulthood (Huber and Gross 1989; Mayer-Gross 1932). Most individuals who...

Here is a structured Markdown conversion of the provided document. # Chapter 2 # Natural History * Diana O. Perkins, M.D., M.P.H. * Jeffrey A. Lieberman, M.D. Schizophrenia typically emerges in late adolescence to early adulthood (Huber and Gross 1989; Mayer-Gross 1932). Most individuals who develop schizophrenia have a chronic course. However, the severity of positive, negative, cognitive, and mood symptoms is highly variable, as is the course of social and vocational disability. Long-term outcomes range from sustained, complete recovery to severe disability from chronic residual symptoms. In this chapter, we review the stages of illness and the variable course that characterize schizophrenia. We also examine long-term outcomes, as well as factors that impact prognosis, including pharmacological and psychotherapeutic treatments. ## Stages of Illness The natural history of schizophrenia may be conceptualized in stages that include premorbid, prodromal, first-episode, early-course, and chronic phases. The duration, course, and severity of symptoms in each phase are highly variable. ### Premorbid Phase Premorbid phase refers to the period before the emergence of psychotic symptoms. Childhood premorbid features include delayed motor milestones (Filatova et al. 2017), deficits in cognitive function (Mollon et al. 2018), and measured IQ that is on average 8 points lower than expected (Fuller et al. 2002; Khandaker et al. 2011). During adolescence, cognitive functions-especially information processing speed, attention, and verbal memory-further decline (Mollon and Reichenberg 2018; Mollon et al. 2018). Social understanding and social function are also impaired (Niemi et al. 2003). However, the distribution of cognitive and functional deficits overlaps considerably with that in the general population. Thus, in the premorbid period, most individuals who develop schizophrenia are not clearly distinguishable from their peers. ### Prodromal Phase About 75%-80% of individuals who go on to develop schizophrenia experience a prodromal phase, marked by attenuated, subsyndromal, psychotic-like symptoms prior to the onset of frank psychosis (Häfner and an der Heiden 1999). Attenuated psychotic symptoms involve disturbances in thought content, thought process, perception, and abilities to organize thoughts and behaviors that are compelling, are disturbing, and impact function. The symptoms occur relatively frequently, at least several times a month. The main feature that distinguishes attenuated psychotic symptoms from fully psychotic symptoms is retention of insight. The person experiencing attenuated psychotic symptoms understands that the experiences are not real and that his or her "mind is playing tricks." Other symptoms characteristic of schizophrenia, including negative symptoms, typically emerge during the prodromal phase (Piskulic et al. 2012). By the time that prodromal symptoms emerge, cognitive impairments are at the severity level found in persons with first-episode schizophrenia (Bora and Murray 2014). Dysphoric moods, such as depression, anxiety, and irritability, are common; about 75% of persons with attenuated psychotic symptoms meet criteria for a mood or anxiety disorder (Addington et al. 2017). Attenuated psychotic, negative, cognitive, and mood symptoms typically impair a person's ability to function at school, at work, or in social situations, and the functional difficulties are often what brings the person to clinical attention. Much of the decline in social and occupational function associated with schizophrenia occurs during the prodromal phase, prior to the onset of frank psychosis (Velthorst et al. 2017, 2018). It is critical to appreciate that attenuated psychotic symptoms indicate elevated risk but not a certainty of developing a schizophrenia spectrum disorder. Persons with attenuated psychosis meeting research criteria for a high-risk psychosis syndrome have approximately a 25% risk of developing a psychotic disorder within 2 years and about a 30%-35% risk within 5 years of follow-up (Fusar-Poli et al. 2012). Among non-converters, roughly half continue to experience attenuated symptoms and about half experience complete remission of the symptoms (Simon et al. 2013). Interventions alter the likelihood of conversion to psychosis in a person experiencing attenuated psychosis symptoms (Davies et al. 2018). Meta-analyses of psychotherapy studies find moderate effects, with the risk of subsequent psychosis reduced by about half (Devoe et al. 2019; Hutton and Taylor 2014). The results of studies examining antipsychotics have been mixed (Deas et al. 2016). Importantly, antipsychotics are not considered first-line treatment, because the majority of persons with attenuated psychosis are not actually prodromal for schizophrenia and because psychotherapy appears similarly effective without carrying the risks of antipsychotics. Pharmacological interventions targeting glutamate receptors are promising (Lieberman et al. 2018). There are conflicting results from trials that tested whether omega-3 fatty acids prevent conversion to psychosis (Amminger et al. 2010; Cadenhead et al. 2017). ### Onset of Schizophrenia Typically, schizophrenia spectrum disorders, including schizophrenia, schizoaffective disorder, and schizophreniform disorder, emerge in late adolescence or early adulthood, with the period of highest risk in the decade between ages 20 and 30 (van der Werf et al. 2014). The risk of schizophrenia is higher in men than in women prior to age 30, but the risk is higher in women than in men after age 30. Overall, the risk of schizophrenia is slightly (about 15%) higher for men (van der Werf et al. 2014). The emergence of symptoms varies on a spectrum ranging from abrupt, over days to weeks, to insidious, over months to years. For about half of individuals who develop psychotic symptoms, the emergence of psychosis is relatively acute, occurring over a period of a month or less (Harrison et al. 2001). ### Course and End State After the First Episode The course of illness after the first episode of psychosis is variable. Psychotic symptoms may remit or persist at varying levels of severity and may recur or worsen episodically. Associated symptoms, including negative symptoms, mood symptoms, and cognitive impairments, range from being nondetectable to severe. Social and vocational functioning ranges from premorbid levels to severe impairments. The severity of symptoms and level of disability often stabilize after 5-10 years, ranging from chronic severe symptoms and disability to complete recovery and return to premorbid level of function. Persons with schizophrenia have elevated mortality rates; important contributors to this are increased risks of death due to suicide, accidents, lung diseases, and cardiovascular diseases (Olfson et al. 2015). Treatment with antipsychotic medications potentially affects the natural course of schizophrenia, increasing the likelihood of psychotic symptom remission, reducing the risk of relapse, and possibly improving the end state. Studies prior to the antipsychotic era shed light on the natural history of schizophrenia, independent of the influence of antipsychotics. ### Course and End State Prior to Availability of Antipsychotic Medication The clinical criteria used to diagnose schizophrenia are still evolving and are an important consideration because the clinical course varies depending on the diagnostic criteria. Diagnostic criteria used today were shaped by the observations of Emil Kraepelin (1919) and Eugen Bleuler (1934) early in the twentieth century, prior to the availability of antipsychotics. Kraepelin developed the concept of dementia praecox, a syndrome that required psychosis but often included negative symptoms and cognitive impairments. Kraepelin characterized the course of dementia praecox as either episodic or chronic and as typically progressing toward severe disabling symptoms. However, Kraepelin also observed heterogeneity in the end state and noted that a minority of individuals did not have a progressive course and that complete spontaneous recoveries, while rare, did occur. Kraepelin differentiated dementia praecox from manic-depressive insanity, based on prominent mood symptoms and a more benign course in the latter. Eugen Bleuler coined the term schizophrenia to differentiate it from dementia praecox because "the disease needs not progress as far as dementia and does not always appear praecociter, i.e., during puberty or soon after" (Bleuler 1934, p. 373). Bleuler emphasized the cross-sectional presentation rather than the clinical course, with the primary feature of schizophrenia involving disturbances of thought process (delusions, disorganized ideas, poverty of thought) and disorganized speech. The severity of accessory features varied and included disturbances of perception (hallucinations, illusions), affect (mania, depression, anxiety), and cognition (attention, ambivalence, "dementia"), as well as negative symptoms (decreased motivation, blunting of emotions). Bleuler's formulation resulted in the diagnosis of schizophrenia in persons who would today, based on current criteria, be diagnosed with bipolar disorder or depression with psychosis; that is, he included people with disorders that have a better prognosis than does more narrowly defined schizophrenia (Harrison et al. 2001; Modestin et al. 2003). ### Course The contributions of Kraepelin and Blueler provide insights into the course of schizophrenia prior to the use of antipsychotic medications. Both Kraepelin and Bleuler noted schizophrenia's variable course. Kraepelin (1919) observed, "The general course of dementia praecox is very variable" (p. 181), and Bleuler (1934) noted, "This disease may clear up very much or altogether; but if it progresses, it leads to a dementia of a definite character" (p. 373). Kraepelin (1919) described the course of illness in a cohort of 488 patients with whom he had been involved from the early stages of their illness. He found that 74% of patients had a chronic deteriorating course: "In the majority of cases with a distinctly marked commencement a certain terminal state with unmistakable symptoms of weak-mindedness is usually reached at latest in the course of about two to three years" (p. 181). Regarding the remaining patients, Kraepelin reported, "I myself found real improvement in 26% of my cases, when that of the duration of a few months was also taken into account" (p. 181). He gave an example of such an improved patient: *We find the patient who up till then appeared to be quite confused in his aimless activity or his hopeless degradation, all at once quiet and reasonable in every way. He knows time and place and the people round about him, remembers all that has happened, even his own nonsensical actions, admits that he is ill, writes a connected and sensible letter to his relatives. (p. 188)* Kraepelin found that the severity of residual symptoms varied in the patients with improvements, with 16 of 488 (3%) "completely well" (p. 183). Kraepelin (1919) also found that most improved patients eventually relapsed. "The fact is of great significance that the course of the disease, as we have seen, is frequently interrupted by more or less complete remissions of the morbid phenomena; the duration of these may amount to a few days or weeks, but also to years and even decades, and then give way to a fresh exacerbation with terminal dementia" (p. 181). Bleuler (1934) gave a similar description of the course of schizophrenia: *In every course exacerbations may appear at any time, but after the disease has lasted from two to three decades they are pretty rare. Complete arrests of the diseases are not frequent in asylum patients. In the course of decades an increase of the dementia can usually be noted. Among the more mildly afflicted, who maintain themselves outside of asylums, some seem not to go beyond a certain stage of the disease.* *Improvements also may occur at every stage; but they relate primarily, to the accessory symptoms. Schizophrenic dementia itself no longer actually regresses. But to be* sure all acute syndromes show a tendency to disappear, and chronic hallucinations and delusions may also regress, though much more rarely. (p. 190) Other investigators following Kraepelin's diagnostic conceptualization gave similar descriptions of the courses of "dementia praecox." For example, in a 4.5- to 10-year follow-up of a cohort of 571 hospitalized first-episode patients, 65% never improved, remaining chronically symptomatic and severely disabled (Hunt et al. 1938). Psychotic symptoms remitted for 18% and improved for an additional 17% of patients. Half of these patients relapsed and half did not relapse during the follow-up period, with relapses occurring on average 28 months after discharge. The majority (68%) of patients who relapsed became chronically psychotic. Another 5- to 10-year follow-up study of 519 patients similarly reported that 74% experienced a chronic, unremitting course, with most of these chronic patients continuously hospitalized during the follow-up period (Rupp and Fletcher 1940). Psychotic symptoms remitted for 8% and improved for an additional 18%. Relapses occurred during the follow-up period for 38% of the improved patients; 24% of the relapsed patients did not recover. To summarize, the "natural" course of schizophrenia as described by studies early in the twentieth century was variable, with two-thirds to three-quarters of patients experiencing a chronic, deteriorating course. The rest experienced "spontaneous" improvements in the severity of psychosis, ranging from partial to complete symptom remission and generally an improvement in function. Most of the improved patients experienced recurrent episodes, sometimes with good recovery between episodes but more often with further functional deterioration, emergence of negative symptoms, cognitive impairments, and/or residual psychosis, resulting in chronic illness and disability. After a period that varied from a few years to a decade or more, patients who were chronically psychotic sometimes experienced a reduction or remission of psychosis; however, these patients typically remained functionally disabled by negative symptoms, cognitive impairments, and disorganization. ## End State The typical outcome for the majority of patients with schizophrenia prior to the availability of antipsychotic medication involved a progressive deterioration that led to severe impairments in capacity to interact with others and to function independently. Kraepelin (1919) described the terminal states with varying severity of negative symptoms, cognitive deficits, mood symptoms, and psychotic symptoms. Manfred Bleuler, the son of Eugen Bleuler, vividly depicted the range of pathology in his outcome rating scale (Bleuler 1978). He described patients with the most severe end state as those *who never carry on coherent, understandable conversations. They are either mutistic, or they speak in such confusion that, in response to simple questions, an occasionally applicable remark interspersed with confusing nonsense is the best one can expect in the way of a reply, although usually no sensible answers at all can be expected. They either do no work at all, or at best do purely mechanical chores, such as hauling a cart, plucking horse hair, etc., under intensively supervised work-therapy methods. They appear to disregard and to remain indifferent to their surroundings. Any human contact with them is impossible. They require constant care, and usually cause trouble for those who care for them by acts of violence, vocal abuses, noisy behavior, uncleanliness, or their inability to properly and independently care for their bodily needs, etc. (pp. 190-191)* As Bleuler (1978) described, somewhat less severely ill patients "generally behaved as did the seriously idiotic, except that in one respect or another they consistently proved that their mental equipment was better preserved than outward appearance would indicate" (p. 191). Examples include patients who, on occasion, would "thaw out and establish contact"; "unequivocally and regularly reveal thought disturbances, even in conversation on impersonal topics, but who can still communicate in such a way as to convey their thoughts on a subject with reasonable clarity"; or "while remaining totally uncommunicative, still perform hard work or become actively involved in caring for others" (p. 191). Severely ill patients often lived out their lives in institutions. Patients with a mild or moderate end state were able to *maintain a sensible conversation, at least about topics that do not concern their delusional or hallucinatory experiences, despite the fact that definite, schizophrenia symptoms do exist. Their overt behavior is generally normal, and their illness is not immediately obvious if one becomes involved in conversations. They perform useful work. They live either outside the institution or on quiet wards. (p. 191)*