Longitudinal Course of Schizophrenia

Current Psychiatry Reviews, 2011, 7, 000-000 1

1573-4005/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Longitudinal Course of Schizophrenia

Robert G. Bota*,1,2

and A. Preda3,4

1Clinical Assistant Professor of Psychiatry, University of Missouri Kansas City;

2Staff Psychiatrist, Kaiser Permanente,

Riverside, California; 3Health Sciences Associate Professor of Psychiatry, University of California Irvine;

4Research

Psychiatrist, University of California Irvine Neuropsychiatric Center

Abstract: Background: Understanding the course of schizophrenia is essential to improve prophylaxis, early diagnosis,

diagnostic validity, and prognosis.

Method: We completed a comprehensive literature search for longitudinal, prospective and retrospective studies of

schizophrenia. As studies span over almost a century and use different diagnostic criteria to decrease the effect of studies

heterogeneity we reviewed the data organized according to historical periods (institutionalization and deinstitutionaliza-

tion, pre and post neuroleptic periods)

Results: The majority of the longitudinal studies of schizophrenia report that up to 30-50% of patients present with a sta-

ble or favorable course. Interestingly, this moderately positive outcome is de-emphasized in the literature, which most

times focuses on the bleaker outcome of the rest of the patients (50-70%). A number of putative course predictors at the

time of the initial diagnosis have been proposed. However, the current level of evidence about risk and protective factor is

putative rather than clear and convincing.

Keywords: Longitudinal studies, schizophrenia, prognosis, schizophrenia course

INTRODUCTION

Documenting the course of a disease is usually the task of the epidemiologist, who designs prospective or retrospec-tive follow-up protocols with the goal of comparing patients and controls over extended periods of time. In addition, cross sectional studies can be used to refine conclusions or, at times, to develop new hypotheses about course specifiers. Not surprisingly, when different types of studies are pulled together, data heterogeneity is the rule, which is the case for disease course literature. Schizophrenia (SZ) course litera-ture in no exception to that. In addition to such expected het-erogeneity a review of SZ course literature is complicated by what we see as a historical heterogeneity factor, a concept that can be further deconstructed along the following axes: 1. Standard of care; 2. Nomenclature.

STANDARD OF CARE HETEROGENEITY

There have been significant changes in the standard of care for SZ over the last century. Institutionalization versus deinstitutionalization, non-exposure versus exposure to neu-roleptics are only two of the many “standard of care” factors that can affect the course of SZ across different historical periods.

To address such heterogentiy confounders we grouped studies according to historical periods and further, according to the “Standard of Care” specifics, as follows:

*Address correspondence to this author at the Clinical Assistant Professor of

Psychiatry, University of Missouri Kansas City, 1000 E 24th Street, Kansas

City, MO, USA; Tel: 951/898-7010; E-mail: [email protected]

1. Institutionalization, Pre-neuroleptics Studies.

2. Institutionalization, Neuroleptics Studies.

3. Post-institutionalization, Neuroleptic Studies.

We choose 1960 as the landmark separating pre and post neuroleptic periods, and 1970 as the landmark separating institutionalization and post-institutionalization periods.

NOMENCLATURE HETEROGENEITY

The definition of SZ has changed over time further con-tributing to course heterogeneity. Different diagnostic crite-ria for SZ have been used at different times in the history of psychiatry. A patient diagnosed with SZ one hundred years ago might have a different diagnosis today; similarly, a pa-tient with “modern” (e.g. following DSM IV criteria) SZ might have had a different diagnosis 100 years ago.

Over time, SZ studies have used several diagnostic for-mulations, such as the Kraepelinian, Bleulerian, Schnei-derian, DSM (I to IV) and ICD criteria. These systems have some degree of overlap but also differ from one another in significant ways. In addition, several other diagnostic formu-lations, including St. Louis, Taylor, Vienna Research Crite-ria, Research Diagnostic Criteria (RDC), Feighner, Taylor-Abrams, Washington IPSS 12-Point Flexible System, and Astrup's process/non-process distinction have been used in some of the studies, either alone or along with other tools.

The definitions of remission and relapse have also changed over time.

In order to decrease data heterogeneity due to nomencla-ture changes, for any given historical period, we grouped

2 Current Psychiatry Reviews, 2011, Vol. 7, No. 3 Bota and Preda

studies using the similar diagnostic systems and separated studies using different diagnostic criteria.

Our literature review organizes data according to the above historical criteria. We will first present a historically informed review of the literature, then discuss putative pro-tective/favorable and risk factors for SZ course and outcome.

PRE-ANTIPSYCHOTIC ERA INSTITUTIONALIZA-

TION STUDIES

Harris and Lublin [1] using Kraepelin’s diagnostic sys-tem, followed a cohort of 289 patients over 18 years, and reported a stable, favorable outcome in 44% of patients, while 56% presented a poor outcome. Achte and Apo identi-fied two groups of patients diagnosed with schizophrenic psychosis, the first group hospitalized between 1950 and 1952 (before the neuroleptic era) and the second group hos-pitalized between 1957 and 1959 (neuroleptic era). They reported that the percent of patients without improvement was higher in the 1950–1952 group [2, 3]. In their sample of 294 SZ patients followed for 16 to 17 years in the first quar-ter of last century Mayer-Gross [4] reported that 42% of their sample subjects remitted.

Freyhan [5] reports on two groups of 100 patients each, one hospitalized in 1920 and the other one in 1940, both fol-lowed until 1953. In the first group, 24% of the patients were no longer hospitalized, 65% of the patients were still hospi-talized and 11% were dead 33 years later. In the second group the majority of the patients (53%) were no longer hos-pitalized, 43% were still hospitalized and 4% were dead 13 years later.

Using a sample of 484 patients hospitalized between 1913-1940 with follow-ups of at least 5 years retrospectively diagnosed by DSM IV criteria Stephens et al. reported that 13% were rated as recovered, 29% were improved and 58% were unimproved [6].

Noreik et al. [7] reported on two cohorts of SZ patients: one hospitalized between 1938-1961, and another cohort (acute onset) hospitalized between 1955-1957. After 22 years 16% of patients recovered, 38% improved (including the relapse remitting course), and 46% did not improve. Us-ing Feighner’s criteria Tsuang and Winokur [8] reported on 139 patients admitted during 1934-1944. After a 35 years follow-up 19% of patients recovered, 35% partially im-proved , and 47% were unimproved.

In a 10-year prospective study of 88 DSM II criteria SZ patients criteria Bland and Parker [9] reported the following outcomes: 58% of the patients had no social or intellectual deficits, 51% patients had normal economic productivity, 68% had fair to good social adjustment, and only 8% of pa-tients were unremitting and institutionalized.

The prospective Swiss Burghölzli Hospital Study [10] conducted over 23 years reported on a sample of 208 out of 653 patients with SZ hospitalized between 1942 and 1943. Using a narrower version of diagnostic criteria as compared with Eugen Bleuler, Manfred Bleuler found that 53% of pa-tients either recovered or were significantly improved, and 46% of the sample had minimal or no impairment in social functioning.

POST-ANTIPSYCHOTIC ERA INSTITUTIONALIZA-

TION STUDIES

In another Swiss study Ciompi and Muller [11], exam-ined the effect of aging on schizophrenia. The investigators selected a sample of 289 out of 1,642 SZ patients, meeting the following inclusion criteria: 1. first psychiatric admission before the age of 65, and 2: age: older than 65 in 1963. These patients were diagnosed initially using criteria of Kra-epelin and E. Bleuler and M. Bleuler. The average duration of individual follow-up was 37 years. After 1963 47% of patients had a “short”, i.e. less than 1 year one hospitaliza-tion, while 23% percent of the patients required long term, i.e. over 20 years long, hospitalizations. Undulating course types were described in half of the patients, with 27% of patient recovered and 23% mildly dysfunctional at follow-up. Only 24% of patients were in the moderate-severe cate-gory and 18% in the severe category, with 9% of patients course described as “uncertain”.

The Vermont Longitudinal Research Project [12, 13] was a 32 years long cohort study of 269 patients diagnosed with SZ according to DSM I criteria. The initial cohort patients were “middle aged, poorly educated, lower class individuals further impoverished by repeated and prolonged hospitaliza-tion”. Further, all subjects met a “chronicity criterion” de-fined as being disabled for 1 year at the time of entry in the study. The study initial findings of “half to two third of pa-tients being improved” at follow up were considered at odds with the view about the chronic long term course of SZ. To answer the question about the contribution of the more re-laxed DSM I criteria to this overtly positive outcome, the data was re-analyzed retrospectively study using more strin-gent DSM III criteria. From the original cohort of 269 pa-tients, 118 retrospectively met the DSM III SZ criteria. Out-come was rated using the Strauss-Carpenter Levels of Func-tioning Outcome Scale [14]. Interestingly, even in the more stringently defined DSM III cohort the majority of the sub-ject were improved 32 years later. Specifically for “one half to two thirds of the patients the long term course was neither downward nor marginal but a evolution into various degrees of productivity, social involvement, wellness, and competi-tive functioning.” Also of interest, the study reported that about 50% of the patients were stable at follow-up despite not using psychotropic medications.

Huber et al. [15] studied 758 patients admitted between 1945 to 1959. Of these, 502 patients were followed for up to 14 years (1967 - 1973). Of this sample, 77% received the diagnosis of SZ using the first-rank symptoms and 23% us-ing second-rank (expression) symptoms. The average dura-tion of illness was 22.4 years at the time of the last follow-up. At the end of the study the vast majority of the subject (87%) lived in communities and were not permanently hos-pitalized. Overall, 22.1% of the patients were in remission, 43.2% had ”pure residual syndromes” and ”structural de-formity without psychosis”, and 34.7% had characteristic residual syndromes [16]. The authors concluded that “predic-tions are possible only when several factors that have a simi-lar influence on the long-term prognosis occur in combina-tion, and when factors with contrary prognostic influence are absent. Even under these circumstances, the individual

Longitudinal Course of Schizophrenia Current Psychiatry Reviews, 2011, Vol. 7, No. 3 3

course is by no means certain”. The long-term prognosis appeared to be independent of the duration of illness.

Retterstöl [17] followed 94 patients diagnosed with SZ at the time of their first admission and 47 patients with a diag-nosis of schizoaffective disorder. They reevaluated these patients approximately 10 years later. Opjordsmoen [18] evaluated 110 of these patients (diagnosed with SZ) 31 years after the first hospitalization and found that short-term hospi-talization correlated with better outcomes than long term hospitalization. Gender did not differentiate outcome at the 10 year follow-up, but women had deteriorated more at the final (31 year) follow-up. At the first follow up 65% subject were without psychosis as compared to 44% at the last ex-amination. DSM III diagnoses appeared to have prognostic value. Specifically DSM III schizoaffective psychosis had a better prognosis than schizophreniform disorders which had a better prognosis than schizophrenia. Approximately one third of patients with Kraepelin’s paranoia had no psychosis at the last follow up. In their sample of 58 schizophrenia patients Breier et al. [19] found that 20% had a good prog-nosis and 78% had at least one relapse at 2 to 12 years fol-low up.

Endicott et al. [20] tested 7 different diagnostic systems in terms of short-term SZ outcome predictors and reported that no system or symptom strongly predicted prognosis, but DSM III and Schneiderian First Rank Symptoms performed better than other systems. However, other studies found that the broader DSM II criteria resulted in a better prognosis than then more stringent DSM III diagnostic criteria [21], meaning that DSM III definition captures a more chronic form of SZ. Of note, the authors proposed that some of the predictive factors (e.g. gender) had a higher predictive value, because a number of the female patients with better progno-sis did not meet the stricter DSM III criteria for inclusion in the study. Patients diagnosed with SZ using DSM III were more homogenous and had a worse prognosis overall [22]. This view was also supported by Servaes [23].

Modestin et al., used clinical notes and patient charts from the 1972 Bleuler study [24] to reassess prognosis after re-diagnosing patients based on DSM III and IV, ICD 10, RDC, Schneider criteria’s, and an operationalized version of Eugen Bleuler’s criteria. The diagnosis of SZ was not con-firmed for 30% of these patients; most of these patients were re-diagnosed with schizoaffective disorder (37% to 66% depending on the tool used). The study found high diagnostic agreement between the DSM III and IV, ICD-10 and RDC schemes, but not with Schneider’s and Bleuler’s criteria. Slightly worse course trajectories were reported when the patients with a confirmed SZ diagnosis were analyzed sepa-rately (145 out of 205 patients), with a decrease in the pro-portion of patients with undulating course and recovery, and a slight increase in the proportion of patients with severe end state. However, even for the SZ patients with a strictly de-fined diagnosis, remission was reported for 12-15%, while an undulating course was reported in about 50%.

DE-INSTITUTIONALIZATION STUDIES

Carpenter et al. [25], utilizing the International Pilot Study of Schizophrenia's Washington cohort, looked at the

prognostic variables for 40 SZ patients followed for 11 years after their index hospitalization and reported that initial prognostic variables were better predictors of long-term out-come than cross-sectional symptoms. With regards to course Carpenter et al. found that a plateau is reached early in the course, while an equal number of patents either improve or deteriorate long-term.

Similarly Eaton et al. longitudinal SZ study found that hospitalizations cluster early in illness, with an amelioration in symptoms occurring over time, when adjusted for the chronicity [26].

Prudo and Blum [27] London based study of 100 hospi-talized SZ patients found that 49% had good symptomatic outcome and 42% had a good social outcome at a 5 year fol-low-up.

Based on the Schizophrenia Health Outcomes (SOHO ) study, a 3-year prospective observational study of outpatients with a diagnosis of SZ, Haro et al. [28] defined three distinct SZ courses: a prolonged course with no remission; remission followed by relapse; and persistent remission. Conducted in 10 European countries, with 1096 participating psychiatrists and 5950 analyzed patients (out of an original sample of 6770 patients) SOHO is one of the largest longitudinal SZ studies to date. During the 3-year follow-up 48% of the pa-tients achieved and maintained remission (persistent remis-sion), 16% achieved remission but relapsed (remission and relapse) and only 39% of the patients presented with a pro-longed course. A number of factors correlated with course: gender, social functioning at baseline (living independently, in paid employment, socially active or being in a relation-ship), and mean duration of illness (years since onset), with female gender, better social functioning, and shorter duration of illness associated with better course. Higher symptom severity at baseline correlated with prolonged course. Pa-tients with a psychotic relapse and longer duration of illness had fewer chances to recover than patients with a shorter course of illness. In short, Haro et al. concluded that a com-bination of remission and relapse periods provided a richer description of SZ course than the use of simple dichotomous outcomes.

In a comprehensive review of literature regarding the outcome of DSM III schizoaffective disorder, Harrow and Grossman [29] report that the prognosis of schizoaffective disorder is better than in SZ but worse than in affective dis-orders. Harrow and Grossman also suggested that mood in-congruent psychotic symptoms are associated with either poor prognosis or with other factors that are suggestive of a poor prognosis. This view is also supported by Shanda et al. [30] study of 90 patients followed for 6-9 years and evalu-ated using a polydiagnostic approach.

At the same time, there are dissenting opinions about the diagnostic stability or better prognosis of schizoaffective disorder compared to schizophrenia. In their 7-year longitu-dinal study of 186 patients diagnosed with functional psy-chosis based on ICD-9, RDC and DSM-III schemes, Lenz et al. [31] reported significant diagnosis stability for schizo-phrenia but not for schizoaffective disorder. Within the schizoaffective group a diagnosis of schizoaffective bipolar

4 Current Psychiatry Reviews, 2011, Vol. 7, No. 3 Bota and Preda

appeared to have better stability than schizoaffective de-pressed. Further, Tsuang and Coryell [32], in an 8-year fol-low-up study, showed that the outcomes for schizoaffective disorder and SZ, diagnosed using DSM III R, were similar.

Negative symptoms have been associated with deficits in functional outcome and poor treatment response [33]. The deficit syndrome, defined as the presence of primary and enduring (>1 year) negative symptoms [34, 35], does not respond well to current pharmacological and psychosocial treatments [36-38]. In previous longitudinal studies of persis-tently impaired SZ patients, the presence of deficit syndrome correlated with poor long-term outcome, worsening of nega-tive symptoms, and possibly an increasing severity of disor-ganized symptoms over time [39-42].

Strauss et al. [43] compared SZ and nonpsychotic de-pressed patients on symptom progression, functional out-come, and recovery over a 20-year period. Deficit syndrome patients were more likely to experience a persistently im-paired course of illness and had poorer long-term outcome than nondeficit SZ patients. More specifically, deficit syn-drome patients had increased disorganized thinking and greater worker disability over time. Global recovery was seldom achieved among deficit patients and was even less likely later in the course of the illness.

Using a prevalence survey Harvey et al. assessed 28 pre-dictors and several categorical and continuous outcome measurements for 114 community-dwelling SZ patients over 5 years and reported that the majority of the patients (62%) were better overall at the end of follow-up period, with only a little more than a third (33%) of patients being worse. While negative symptoms per se were not assessed, social isolation and being apart from relatives, in addition to longer illness and being hospitalized at the time of the first assess-ment, accounted for a third of the variance in outcome [44].

Mancevski et al. examined data from the onset of illness until death for 99 chronic SZ inpatients that lived and died in state institutions [45]. The study found that the lifetime course of SZ in chronically institutionalized patients is char-acterized by decreased positive symptoms and increased negative symptoms. Earlier onset (before the age of 25) SZ presented with more negative symptoms throughout life.

Schultz et al. [46] charted the lifetime course for 3 symptom dimensions (psychotic, disorganized, and negative) in SZ patients aged 14 – 73 and reported a negative correla-tion between age and positive and disorganized symptoms, where age was associated with a decrease in hallucinations, delusions, bizarre behavior, and inappropriate affect. Nega-tive symptoms showed a gender (males worse than females) but not age effect. Schultz et al. concluded that psychotic and disorganized symptoms were likely to be of lesser sever-ity in older patients, while negative symptoms tended to per-sist.

To summarize, the evidence suggests that positive symp-toms can improve overtime while the negative symptoms lifetime course is one of either stability or worsening.

Cognitive impairment is another symptoms cluster that has been followed longitudinally. Interestingly, Hoff et al.

[47] found that cognitive changes occur prior to the onset of SZ. Longitudinal studies report long-term stability (from 4 years [48] to 10 years [49]) of cognitive impairment in schizophrenia.

Bergstein et al. [50] studied the relationship between

sense of coherence (SOC), expressed emotion (EE), depres-

sion, and delusions as prognostic factors. In an 18 month

follow-up study of 48 acutely delusional SZ patients they

found that 23 % had stable remission, 8% had late remission,

23% had a chronic course, and 42 % relapsed after initial

improvement. The SOC was strongly correlated with delu-

sional symptoms, with higher SOC scores during the acute

delusional state indicative of a better prognosis for this pa-

tient population.

The Danish National Schizophrenia Project [51, 52], a

prospective, comparative, longitudinal study with a mini-

mum intervention period of 2 years assessed patients with a

first episode of a SZ spectrum disorder at baseline and at 1, 2

and 5 years follow-up. Patients (N=562) were randomized to

3 treatments: 119 patients to supportive psychodynamic psy-

chotherapy (PP), 139 to an “integrated treatment (IT)”, a

program consisting of assertive community treatment, psy-

choeducational multifamily treatment, social skills training,

and antipsychotic medication, and 304 to “treatment-as-usual

(TAU)”. The three cohorts were similar at baseline. After

one year, patients in the 2 intervention groups improved

more in terms of symptoms and social function than patients

in the TAU group. This improvement continued into the sec-

ond year. Patients that received IT fared better than those

treated with PP, which suggests that more intensive psycho-

therapeutic modalities may improve the outcome for patients

with first psychotic episodes.

A naturalistic study of 280 patients with SZ (DSM-IV

criteria) treated with antipsychotics for 8 weeks reported that

78.5% of the subjects responded and 44.6% remitted, where

remission and response were defined according to Remission

in SZ Working Group consensus [53]. Thirthalli et al. [54]

prospective longitudinal study of 215 SZ (ICD-10 criteria)

patients, comparing medicated and non-medicated patients

during a 1 year follow-up. Disability scores were higher in

patients who were not treated with neuroleptics at baseline

and remained stable (and high) for those who choose to not

take medications for the study duration. In addition, disabil-

ity scores improved for the subjects who either continued to

receive antipsychotics or agreed to take antipsychotic treat-

ment during the study.

Using a largely community based sample Harvey et al.

[44] evaluated 114 SZ patients found that 62% of the pa-

tients were better overall, while 33% were worse at a five

year follow-up. There were 4 best negative predictors of out-

come: social isolation, longer illness, living apart from rela-

tives, and being an inpatient at first census, which together

accounted for 32% of the outcome variance. The authors

concluded that social relationships during the course of the

illness were important predictors of overall outcome. Fur-

thermore, relationships with friends and family also posi-

tively contributed to a better outcome.

Longitudinal Course of Schizophrenia Current Psychiatry Reviews, 2011, Vol. 7, No. 3 5

PUTATIVE PROTECTIVE AND RISK FACTORS

Demographic Factors

Gender and Age

A number of studies report that women with SZ might have a milder course of illness than men [12, 55-58]. The male/ female risk ratio has been estimated at 1.4/1 [59] sug-gesting an increase in risk for males. Interestingly, flat affect, which has been associated with poorer prognosis, is more prevalent in men [60-64].

Grossman et al. examined the gender differences on the course of SZ in a 20-year long, prospective longitudinal study [65]. Ninety-seven patients, 43 women and 54 men, were assessed during index hospitalization (acute phase of the illness), and re-assessed prospectively, at 6 consecutive follow-up visits. Compared to men, women had a lower per-centage of psychotic episodes over the course of the illness and a significant improvement in psychotic activity over 20 years. In addition, women showed significantly better global function, higher percentages of recovery, and a greater per-centage of a having a period of recovery at some point dur-ing the 20 year period (61% women versus 41% for men).

Of note, a retrospective analysis of 10-year follow-up data collected in 110 SZ patients reported no difference in clinical outcomes of men versus women at the final follow up [18]. Interestingly, women rated better than men at the time of the initial assessment but also deteriorated more than men during the 10 year follow-up period. In addition, Ciompi and Miiller's [11] 36.9-year follow-up study of 289 patients found 49% achieved a favorable overall "end state", with a male to female ratio of 57.6% to 44.7% among those improved [66]. However, women maintained a slight edge in long-term symptom remission (21.7% vs. 19.4%) [66].

Race

No variation in prevalence has been found with certainty between ethnic groups

28.

Clinical Course Related Factors

A shorter duration of symptoms and functional deteriora-tion before the hospitalization (e.g. acute onset and work history) improve prognosis [67-69], while earlier onset, more insidious debut and absence of perceived stress at onset are associated with worse prognosis [70].

Past History Related Factors

Past Psychiatric History Related Factors

Patients diagnosed with developmental language disorder as children demonstrated a 6.4% risk of developing schizo-phrenia spectrum disorders vs. 1.8%; P < 0.0001 in general population [71].

Past Substance History Related Factors

Substance misuse has been reported to be the most preva-lent comorbid condition associated with schizophrenia [72]. Cannabis is the most frequently used substance [73] and SZ patients have significantly higher rates of abusing marijuana when compared to the general population or patients with other mental illness [74]. However it is unclear if cannabis

use is a risk factor reflecting a cause and effect relationship, an increase of risk for use for those already at risk for devel-oping a psychotic disorder [75-78], or a protective factor (where increased use is due a putative beneficial effect on psychotic symptoms) [79].

Physical Factors

In a large (over 1.3 million men) longitudinal Swedish study both height and BMI in young adulthood were strongly and inversely correlated with the risk of developing schizo-phrenia [80].

Family History

While a negative family history of mental illness has been associated with a better outcome [67-69], a family his-tory of SZ is a strong risk factor [81, 82]. While there is no one risk factor for developing SZ [83] the closer the family relationship to an affected relative, the higher the risk for schizophrenia [84, 85]. While high heritability has been con-sistently found in family, twin and adoption studies, the ge-netics of schizophrenia are complex and place the individual on a risk continuum that is mitigated by important epigenetic factors [85]. Different deficits may be linked to genes and some symptoms are found in asymptomatic relatives of pa-tients with schizophrenia (e.g., poor psychosocial function-ing, change in brain volume over time) [86-88]. Family his-tory has a small but significant effect on decreasing the age-at-onset, as well as increasing the risk for negative symptoms [89].

Mental Functioning Related Factors

Emotional Processing Related Factors

The presence of affective symptoms at hospital admis-sion is a favorable prognostic factor. [67-69] Perception of emotion in patients with SZ has been correlated with better work functioning and independent living at one year, but not with social functioning and family relationships [90].

Insight Related Factors

Antonovsky and Sagy describe a “sense of coherence” (SOC) concept [91] as a potentially favorable prognostic factor. SOC defines the individual ability to maintain psy-chological well-being, including manageability, comprehen-sibility, and “meaning”. Bergstein suggested the use of SOC scale as prognostic tool in acute delusional states and rec-ommends specific interventions aimed toward improving the SOC score [50].

Suddendorf describes “foresight” as the ability to con-sider the long-term effects of behavior to guide present and future actions as they relate to a functional outcome [92]. Eack and Keshavan [93, 94] found that the baseline level of foresight predict functional outcome, even after adjusting for psychopathology, treatment received and neurocognitive functioning [95].

Cognitive Factors

Cognitive impairments appear to be fully developed at the time of the first episode of illness in those individuals who develop schizophrenia. Comparisons with more chronic patients reveal similar profiles and severities of impairment,

6 Current Psychiatry Reviews, 2011, Vol. 7, No. 3 Bota and Preda

suggesting that progression may not be common during the early course of illness. A 10-year longitudinal study demon-strated the stability of baseline cognitive deficits in first epi-sode (FE) patients compared with a group of healthy controls [49]. A recently published comprehensive meta-analysis reports significant deficits in FE patients compared to their prior premorbid levels but a stable, chronic course after as well as no significant differences when comparing deficits in FE and chronic schizophrenia patients [96]. Another recent and methodologically sophisticated study, of high risk, first-episode, and healthy individuals followed up over 6-month found that a higher than expected proportion of FE patients improved on their verbal memory performance and a higher proportion than expected worsened in processing speed and working memory. Further, the at-risk subjects who converted to psychosis were also found to worsen in these same two variables [97].

While the course of cognition in schizophrenia in early and mid life might be more stable, there is evidence that a least some people with schizophrenia show deterioration in their functioning in their later years. Patients with a history of long-term institutional stay and extremely severe and re-fractory positive symptoms have been shown to have subtle worsening in their cognitive functioning over a variety of follow-up periods [98].

Higher metacognitive ability of schizophrenia patients correlates with better work performance [99]. General cogni-tive ability (measured by intelligence quotient) has been positively correlated with functional outcome [100]. Subjects with higher IQ appear more liable to have deterioration at the first hospitalization but return to the previous level at ten years reassessment, while the subjects with lower IQ main-tained a more stable score over the observed period [101].

In a recent meta-analysis (53 studies, regardless of types of medication used) of longitudinal studies of cognition, Szoke et al. [102] report that schizophrenia patients demon-strated a significant improvement in most cognitive tasks with exception of Stroop test. Performance in semantic ver-bal fluency was stable in both controls and patients with schizophrenia, thus suggesting that it could be the best can-didate cognitive endophenotype.

Self Concept Related Factors

Self-efficacy and self-esteem correlated positively with the general quality of life in schizophrenia patients [103].

Clinical Factors

Negative Symptoms

Andreasen’s negative symptoms, Crow’s type II, and Carpenter’s deficit schizophrenia are all characterized by an insidious onset [33, 34, 104-107]. Negative symptoms are fairly prevalent in first episode patients with schizophrenia, with estimated rates of 35-70% during relatively short (less than 2 years) longitudinal studies [108-110].

Primary negative symptoms have been associated with poor premorbid function, male gender and low IQ [105]. Male gender increases the risk for negative symptoms; in addition, male schizophrenia patients have been reported to

have more severe negative symptoms [111, 112]. Men also present more frequently with flat affect than women patients with schizophrenia [60-64]. In a multicenter retrospective study of 1452 patients diagnosed with SZ spectrum disorders 57.6% of patients had at least one negative symptom, while primary negative symptoms were reported in 12.9% of pa-tients [113]. As expected, SZ patients had more frequent and more severe negative symptoms than patients with a diagno-sis of schizophreniform or schizoaffective disorder [113]. Persistent negative symptoms were more prevalent in SZ than in depressed patients and seemed to correlate with de-pressive symptoms [109]. In a long-term prospective study of SZ spectrum disorders the prevalence of negative symp-toms was found to be high at the 15 year follow-up: 75% of the SZ patients, 68% of the schizoaffective patients, and 44% of the patients with affective disorders where found to have at least one negative symptom [114]. However, SZ pa-tients had much more severe negative symptoms at the 15 year follow up compared to both the schizoaffective and affective disorder controls [114, 115].

Negative symptoms appear to be persistent but likely to increase with age [62]. In a cross sectional study of 272 SZ patients divided in 4 age groups, aging was associated with increased symptom severity [63]. In a retrospective study of 99 chronically institutionalized patients, the lifelong course of SZ was characterized by a decrease in positive symptoms and an increase in negative symptoms [45]. Putnam et al., in a prospective 1 year-long study of geriatric inpatients with schizophrenia, reported a significant increase in negative symptom severity over the study period [116].

Social Factors

In a 18 month prospective study Ritsner et al. [103] showed that social support correlated positively with the general quality of life in schizophrenia. A higher disease incidence has been reported in urban and low-income popu-lations versus rural and higher income groups [117-119]. Migrant status [120] in countries with higher immigration has a higher risk than migrant status in countries with lower immigration [121].

Environmental Factors

Affected persons have been found to be more likely to have been born in the winter versus the spring or summer seasons, but this data is controversial [122, 123]. No varia-tion in prevalence has been found with certainty between ethnic groups [124]. A higher prevalence has been suggested in the northeastern and western regions of the U.S. [125].

DISCUSSION

The majority of the longitudinal studies in schizophrenia report that up to 30-50% of patients present with a stable and even favorable course, rather than gradually deteriorating (Table 1). Interestingly, even longitudinal studies in the pre-antipsychotic era support this conclusion. For example, using Kraepelinian diagnostic criteria, 42 % of patients showed remission in a 16 years study at the beginning of 20st cen-tury [1], while in another 20 years long study [5] (1920 to 1940,) 35% and 57% respectively were not hospitalized 13 years later [5].

Longitudinal Course of Schizophrenia Current Psychiatry Reviews, 2011, Vol. 7, No. 3 7

The development of neuroleptic medication contributed significantly to deinstitutionalization by allowing a faster stabilization period but did not prove to be superior when compared to previous interventions in preventing hospitali-zation at 1 year post-discharge [126]_ENREF_65_ENR-EF_65_ENREF_65_ENREF_65_ENREF_65 or clearly im-proving long-term course or prognosis. Torgalsboen and Rund [127], reported that only half of the patients diagnosed with remission 10 years before maintained a recovery diag-nosis.

It is generally accepted that the use of antipsychotic medications can improve prognosis [2, 3] or decrease the level of disability [54]. Also, in addition to medications, pa-tients receiving comprehensive treatment [51, 52], integrat-ing assertive community treatment, psychoeducational multi-family treatment, and social skills training fare better than those being treated with supportive psychodynamic psycho-therapy or “treatment as usual”. There are suggestions that early treatment during the ultra-risk period of the prodrome of SZ [128] and at the debut of the illness [129] could im-prove prognosis. The promise of prophylactic intervention is certainly exciting, however the recommendation for early psychopharmacologic intervention is controversial as an es-timated 25-40% of acute psychosis patients remit without the use of antipsychotic medications [130]. Furthermore, newly identified patients with SZ spectrum disorders minimal use of antipsychotic medications combined with psychosocial interventions might be better when compared with patients on continuous medication treatment [131, 132].

The effect of evolving treatments, in addition to other factors (e.g., the individual’s level and perception of stress, alimentation, exposure to toxins and other environmental

factors) need to be carefully considered when data is cap-tured longitudinally, over extended periods of time. Koshland describe a “paradigm challenge” [133] as new data emerges which may be incongruous with the existing theo-ries. Such factors should to at least be acknowledged as pos-sible confounders; in certain cases a more direct, disease modifying effect might need to be considered.

We will use two examples to illustrate this point. First, the oldest longitudinal studies of SZ reported a smaller per-cent of patients lost to follow-up than the more recent studies [4, 5, 27, 45]. Interestingly, this finding cannot be accounted by the longer hospitalizations of the period as, in several of these studies, the patients were traced post hospitalization and in-between hospitalizations. This is a case were other confounders should be considered, such as changes in the nature of the therapeutic relationship (with a more authoritar-ian physician stance in the past), or the nature of family dy-namics (with more “connected” extended families in the past) among others. A different example: the cases of cata-tonic SZ seem to have decreased over time [134]; a rather drastic change in a clinical phenotype. In this case, in addi-tion to considering confounders, one might also consider a more direct effect of a potentially disease/phenotype/gene expression modifying factor (i.e., a cumulative medical treatment/other interventions effect at the individual and his/her offspring’s level).

To illustrate, out of a group of patients with frequent hospitalizations over a period of 4 years, those offered boarding homes (with an average stay of 11 months) had significantly less hospitalizations days during the boarding home period and years after, as well as a lower hospitaliza-tion rate [135] than a non-boarding home control group. It

Table 1. Relative Change (Better/worse)

Improvement Deterioration/-

Unimproved

Recovered/-

Remission

Sample Size Duration of Study

Camden schizophrenia

Surveys [44]

62% 33% 114 5 years

Prudo and Blum [27] 49% 100 5 years

Tsuang and Winokur [8] 35% 47% 19% 139 40 years

The Burgholzli Hospital

Study [10]

53% 46% 208 23 years

Noreik et al. [7] 38% 16% 148 22 years

The Vermont Longitudi-

nal Research Project [12,

13]

Another 34% 34% 269 32 years

Huber et al. [15] 43.2% 22.1% 502 14 years

Breier et al. [19] 20% 58 2 to 12 years

The SOHO study [28] 38.7% 45.7% 5950 3 years

Bland and Parker [9] 69% 17% 51% 88

10 years

Carpenter et al. [25] 50% 50% 40 11 years

8 Current Psychiatry Reviews, 2011, Vol. 7, No. 3 Bota and Preda

should be acknowledged that the protective effects of struc-ture have been demonstrated over decades.

In terms of the stability of improvement, McWalter et al. [126] reports that 46% of patients in the pre-neuroleptic era and 49% of patients in post-neuroleptic era were not read-mitted during the year following discharge. Although a shorter duration of symptoms is noted with neuroleptic ther-apy, the time to rehospitalization is not significantly in-creased, when most of other factors are the same.

The changes in diagnostic criteria over time effectively parcel an apparently homogeneous entity in smaller and likely different biopsychological constructs. Conceivably the differences between such constructs will manifest in differ-ences of course and prognosis. Stephens et al. [136], using 9 diagnostic systems to analyze the records of 283 hospitalized patients discharged with a diagnosis of SZ, schizoaffective disorder and paranoid state, found that only 3 schemes (the New York Research Diagnostic Criteria (RDC), DSM III, and St. Louis criteria), had high diagnostic agreement.. Modestin [24] reported diagnosis agreement between DSM III and IV, ICD-10 and RDC but not with either Schneider’s or Bleuler’s criteria. Lenz et al [31] also reported that there good diagnosis stability with the ICD-9, RDC and DSM III systems. However, in another study [20], , only two (DSM III and Schneider’s first rank) out of 7 tested diagnostic sys-tems performed better in predicting prognosis. One study suggested that SZ diagnosed with DSM II might have a bet-ter prognosis when compared with SZ according to the DSM III system [21].

With both over and under inclusive criteria, i.e. a broad or narrow diagnosis, only time can reveal the different sys-tems long-term strengths and shortcomings.

CONCLUSION AND FUTURE DIRECTIONS

Our review of the literature indicates that 22-34% of SZ patients recover, 24-46% have moderately severe outcome, and 18-35% of patients have a severe outcome, [12, 13, 15, 24, 28, 50, 137, 138]. The percentage of patients having a particular outcome largely depended on the type of SZ, with worse prognosis reported for hebephrenic type (55% unim-proved) and process status (54% unimproved at follow-up) [139]. In the earliest longitudinal studies [140] 39% of the patients admitted for the first time with SZ continued to be hospitalized at 5 years. In general, using similar diagnostic criteria, reported recovery varies between 16% [7] to 45.7% [28] while improvement in outcome could as high as 69% [9]. Interestingly, this moderately positive outcome is de-emphasized in the literature, which most times focuses on the bleaker outcome of the rest of the patients.

For most patients SZ seems to move through the stages of premorbid, prodromal, and psychosis, where psychosis also progress through acute phase/crisis, stabilization phase, and stable/maintenance phases {see [141, 142] for a review]. The positive symptoms tend to attenuate over times, cogni-tive deficits remain stable, while the negative symptoms ei-ther remain stable or change for the worse.

DSM IV and ICD, the most used SZ diagnostic schemes, offer good reliability and uniformity in diagnosis, as well as

a sense of general consensus regarding the diagnostic ap-proach. However the current categorical approach has a number of shortcomings, some illustrated by a course het-erogeneity not supported by epidemiological, clinical, and biological data. A dimensional alternative would help reduce heterogeneity and improve the predictive power of diagnos-tic criteria.

Our findings echo Fenton and McGlashan’s impression from almost a quarter of century ago: “it [still] is far easier to predict which patients will do poorly than it is to predict, with much power, those who will do well” [143].

But our most important conclusion is that while is ap-pears to be true that for a number of patients SZ course is chronic and marked by progressive worsening, the percent-age of worse prognosis patients is less than half. In other words, the majority of studies indicate the most patients (40-60%) recover partially or completely. This conclusion how-ever is not universally agreed upon; e.g. Robinson et al., in a prospective longitudinal study of 104 SZ patients previously recovered, report an 82% relapse rate by the end of a 5-year follow-up [144].

At the same time, our less pessimistic findings about course have important consequences in terms of both diag-nosis and intervention: e.g. early diagnosis can justifiably be conceptualized as a premise for success rather than as a con-demnation to the gallows. The combination of tools available for early assessment and intervention and a more optimistic perception of course and prognosis will hopefully enable a more realistic calibration of what appears to be an unjustifia-bly negative perspective on SZ course and prognosis.

The major weakness of a review such as ours is that its conclusions are limited to the qualities of studies available for review. Course studies are very rarely life-long studies; thus, one needs to cautiously consider concepts such as re-sponse, recovery, and remission. With the exception of life-time studies, long-term studies report on essentially limited periods of time, i.e. alternative outcomes can conceivably unfold following the official completion of the study. Spe-cifically, to differentiate between remission and recovery might be tricky when the study provides only for a short fol-low-up period. In addition the very definitions of response, remission, and recovery have changed over time and most of the older literature do not give enough details for a proper determination about how such and related concepts were defined at the time.

Clearly, further prospective, long-term and preferentially life-time studies, with carefully validated diagnostic criteria, including endophenotypes (e.g., cognitive and negative symptoms clusters, EEG, electrophysiology and brain imag-ing data) in addition to clinical criteria, are recommended to clarify the course and prognosis of schizophrenia.

REFERENCES

[1] Harris AaL, A. The prognosis of the functional psychosis. Monatsschrift fur Psychiatrie und Neurologie. 1954; 124: 126-45.

[2] Achte KA, Apo M. Schizophrenic patients in 1950-1952 and 1957-1959. A comparative study. The Psychiatric quarterly. 1967 Jul;

41(3): 422-41. [3] Achte KA. On prognosis and rehabilitation in schizophrenic and

paranoid psychoses. A comparative follow-up study of two series

Longitudinal Course of Schizophrenia Current Psychiatry Reviews, 2011, Vol. 7, No. 3 9

of patients first admitted to hospital in 1950 and 1960 respectively.

Acta psychiatrica Scandinavica. 1967; 196: 1-217. [4] Mayer-Gross W.[Selective outcome resulting from psychological

and Physical damage]. Berlin: Springer 1932. [5] Freyhan FA. Course and outcome of schizophrenia. Am J Psychia-

try. 1955 Sep; 112(3): 161-9. [6] Stephens JH, Richard P, McHugh PR. Long-term follow-up of

patients hospitalized for schizophrenia, 1913 to 1940. The Journal of nervous and mental disease. 1997 Dec; 185(12): 715-21.

[7] Noreik K, Astrup C, Dalgard OS, Holmboe R. A prolonged follow-up of acute schizophrenic and schizophreniform psychoses. Acta

psychiatrica Scandinavica. 1967; 43(4): 432-43. [8] Tsuang MT, Winokur G. The Iowa 500: field work in a 35-year

follow-up of depression, mania, and schizophrenia. Can Psychiatr Assoc J. 1975 Aug; 20(5): 359-65.

[9] Bland RC, Parker JH, Orn H. Prognosis in schizophrenia. A ten-year follow-up of first admissions. Arch Gen Psychiatry. 1976

Aug; 33(8): 949-54. [10] Bleuler M. Die schizophrenen Geistesstorungen im Lichte lang-

jahriger Kranken- und Familiengeschichten. (New-York: Intercon-tinental Medical Book Corp., U.S.distribution) ed. Stuttgart:

George Thieme Velag 1972. [11] Ciompi L, Muller C.[Lifestyle and age of schizophrenics. A catam-

nestic long-term study into old age]. Monogr Gesamtgeb Psychiatr Psychiatry Ser. 1976; 12(0): 1-242.

[12] Harding CM, Brooks GW, Ashikaga T, Strauss JS, Breier A. The Vermont longitudinal study of persons with severe mental illness,

II: Long-term outcome of subjects who retrospectively met DSM-III criteria for schizophrenia. Am J Psychiatry. 1987 Jun; 144(6):

727-35. [13] Harding CM, Brooks GW, Ashikaga T, Strauss JS, Breier A. The

Vermont longitudinal study of persons with severe mental illness, I: Methodology, study sample, and overall status 32 years later. Am J

Psychiatry. 1987 Jun; 144(6): 718-26. [14] Strauss JS, Carpenter WT, Jr. Prediction of outcome in schizophre-

nia. III. Five-year outcome and its predictors. Arch Gen Psychiatry. 1977 Feb; 34(2): 159-63.

[15] Huber G, Gross G, Schuttler R, Linz M. Longitudinal studies of schizophrenic patients. Schizophr Bull. 1980; 6(4): 592-605.

[16] Schneider K. Klinische Psycho-pathologie. 4 ed. Stutgard: Georg Thieme Velag KG 1976.

[17] Retterstol N. Course and outcome in paranoid disorders. Psychopa-thology. 1991; 24(5): 277-86.

[18] Opjordsmoen S. Long-term clinical outcome of schizophrenia with special reference to gender differences. Acta Psychiatr Scand. 1991

Apr; 83(4): 307-13. [19] Breier A, Schreiber JL, Dyer J, Pickar D. National Institute of

Mental Health longitudinal study of chronic schizophrenia. Progno-sis and predictors of outcome. Arch Gen Psychiatry. 1991 Mar;

48(3): 239-46. [20] Endicott J, Nee J, Cohen J, Fleiss JL, Simon R. Diagnosis of

schizophrenia. Prediction of short-term outcome. Arch Gen Psy-chiatry. 1986 Jan; 43(1): 13-9.

[21] Westermeyer JF, Harrow M. Prognosis and outcome using broad (DSM-II) and narrow (DSM-III) concepts of schizophrenia.

Schizophr Bull. 1984; 10(4): 624-37. [22] Harrow M, Westermeyer JF. Process-reactive dimension and out-

come for narrow concepts of schizophrenia. Schizophr Bull. 1987; 13(3): 361-8.

[23] Servaes M. Classification and prognosis of psychoses. Acta Psy-chiatr Belg. 1983 Jul-Aug; 83(4): 368-74.

[24] Modestin J, Huber A, Satirli E, Malti T, Hell D. Long-term course of schizophrenic illness: Bleuler's study reconsidered. Am J Psy-

chiatry. 2003 Dec; 160(12): 2202-8. [25] Carpenter WT, Jr., Strauss JS. The prediction of outcome in

schizophrenia. IV: Eleven-year follow-up of the Washington IPSS cohort. J Nerv Ment Dis. 1991 Sep; 179(9): 517-25.

[26] Eaton WW, Bilker W, Haro JM, Herrman H, Mortensen PB, Free-man H, et al. Long-term course of hospitalization for schizophre-

nia: Part II. Change with passage of time. Schizophr Bull. 1992; 18(2): 229-41.

[27] Prudo R, Blum HM. Five-year outcome and prognosis in schizo-phrenia: a report from the London Field Research Centre of the In-

ternational Pilot Study of Schizophrenia. Br J Psychiatry. 1987 Mar; 150: 345-54.

[28] Haro JM, Novick D, Suarez D, Ochoa S, Roca M. Predictors of the

course of illness in outpatients with schizophrenia: a prospective three year study. Prog Neuropsychopharmacol Biol Psychiatry.

2008 Jul 1; 32(5): 1287-92. [29] Harrow M, Grossman LS. Outcome in schizoaffective disorders: a

critical review and reevaluation of the literature. Schizophr Bull. 1984; 10(1): 87-108.

[30] Schanda H, Thau K, Kufferle B, Kieffer W, Berner P. Heterogene-ity of delusional syndromes: diagnostic criteria and course progno-

sis. Psychopathology. 1984; 17(5-6): 280-9. [31] Lenz G, Simhandl C, Thau K, Berner P, Gabriel E. Temporal sta-

bility of diagnostic criteria for functional psychoses. Results from the Vienna follow-up study. Psychopathology. 1991; 24(5): 328-35.

[32] Tsuang D, Coryell W. An 8-year follow-up of patients with DSM-III-R psychotic depression, schizoaffective disorder, and schizo-

phrenia. Am J Psychiatry. 1993 Aug; 150(8): 1182-8. [33] Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT, Jr. A sepa-

rate disease within the syndrome of schizophrenia. Arch Gen Psy-chiatry. 2001 Feb; 58(2): 165-71.

[34] Carpenter WT, Jr., Heinrichs DW, Wagman AM. Deficit and non-deficit forms of schizophrenia: the concept. Am J Psychiatry. 1988

May; 145(5): 578-83. [35] Wagman AM, Heinrichs DW, Carpenter WT, Jr. Deficit and non-

deficit forms of schizophrenia: neuropsychological evaluation. Psychiatry Res. 1987 Dec; 22(4): 319-30.

[36] Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Sum-merfelt A, et al. Effects of clozapine on positive and negative

symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994 Jan; 151(1): 20-6.

[37] Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT, Jr. Positive and negative symptom response to clozapine in schizo-

phrenic patients with and without the deficit syndrome. Am J Psy-chiatry. 1998 Jun; 155(6): 751-60.

[38] Kopelowicz A, Liberman RP, Mintz J, Zarate R. Comparison of efficacy of social skills training for deficit and nondeficit negative

symptoms in schizophrenia. Am J Psychiatry. 1997 Mar; 154(3): 424-5.

[39] Amador XF, Kirkpatrick B, Buchanan RW, Carpenter WT, Mar-cinko L, Yale SA. Stability of the diagnosis of deficit syndrome in

schizophrenia. Am J Psychiatry. 1999 Apr; 156(4): 637-9. [40] Fenton WS, McGlashan TH. Antecedents, symptom progression,

and long-term outcome of the deficit syndrome in schizophrenia. Am J Psychiatry. 1994 Mar; 151(3): 351-6.

[41] Kirkpatrick B, Buchanan RW, Breier A, Carpenter WT, Jr. Case identification and stability of the deficit syndrome of schizophre-

nia. Psychiatry Res. 1993 Apr; 47(1): 47-56. [42] Kirkpatrick B, Ram R, Bromet E. The deficit syndrome in the

Suffolk County Mental Health Project. Schizophr Res. 1996 Nov 15; 22(2): 119-26.

[43] Strauss GP, Harrow M, Grossman LS, Rosen C. Periods of recov-ery in deficit syndrome schizophrenia: a 20-year multi-follow-up

longitudinal study. Schizophr Bull. Jul; 36(4): 788-99. [44] Harvey CA, Jeffreys SE, McNaught AS, Blizard RA, King MB.

The Camden Schizophrenia Surveys. III: Five-year outcome of a sample of individuals from a prevalence survey and the importance

of social relationships. Int J Soc Psychiatry. 2007 Jul; 53(4): 340-56.

[45] Mancevski B, Keilp J, Kurzon M, Berman RM, Ortakov V, Harkavy-Friedman J, et al. Lifelong course of positive and negative

symptoms in chronically institutionalized patients with schizophre-nia. Psychopathology. 2007; 40(2): 83-92.

[46] Schultz SK, Miller DD, Oliver SE, Arndt S, Flaum M, Andreasen NC. The life course of schizophrenia: age and symptom dimen-

sions. Schizophr Res. 1997 Jan 17; 23(1): 15-23. [47] Hoff AL, Sakuma M, Wieneke M, Horon R, Kushner M, DeLisi

LE. Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia. Am J Psychiatry. 1999 Sep;

156(9): 1336-41. [48] Reichenberg A, Rieckmann N, Harvey PD. Stability in schizophre-

nia symptoms over time: findings from the Mount Sinai Pilgrim Psychiatric Center Longitudinal Study. J Abnorm Psychol. 2005

Aug; 114(3): 363-72. [49] Hoff AL, Svetina C, Shields G, Stewart J, DeLisi LE. Ten year

longitudinal study of neuropsychological functioning subsequent to

10 Current Psychiatry Reviews, 2011, Vol. 7, No. 3 Bota and Preda

a first episode of schizophrenia. Schizophr Res. 2005 Oct 1; 78(1):

27-34. [50] Bergstein M, Weizman A, Solomon Z. Sense of coherence among

delusional patients: prediction of remission and risk of relapse. Compr Psychiatry. 2008 May-Jun; 49(3): 288-96.

[51] Rosenbaum B, Valbak K, Harder S, Knudsen P, Koster A, Lajer M, et al. Treatment of patients with first-episode psychosis: two-year

outcome data from the Danish National Schizophrenia Project. World Psychiatry. 2006 Jun; 5(2): 100-3.

[52] Rosenbaum B, Valbak K, Harder S, Knudsen P, Koster A, Lajer M, et al. The Danish National Schizophrenia Project: prospective,

comparative longitudinal treatment study of first-episode psycho-sis. Br J Psychiatry. 2005 May; 186: 394-9.

[53] Jager M, Riedel M, Obermeier M, Schennach-Wolff R, Seemuller F, Messer T, et al. Time course of antipsychotic treatment response

in schizophrenia: results from a naturalistic study in 280 patients. Schizophr Res. May; 118(1-3): 183-8.

[54] Thirthalli J, Venkatesh BK, Kishorekumar KV, Arunachala U, Venkatasubramanian G, Subbakrishna DK, et al. Prospective com-

parison of course of disability in antipsychotic-treated and un-treated schizophrenia patients. Acta Psychiatr Scand. 2009 Mar;

119(3): 209-17. [55] Angermeyer MC, Goldstein JM, Kuehn L. Gender differences in

schizophrenia: rehospitalization and community survival. Psychol Med. 1989 May; 19(2): 365-82.

[56] Goldstein JM. Gender differences in the course of schizophrenia. Am J Psychiatry. 1988 Jun; 145(6): 684-9.

[57] Seeman MV. Current outcome in schizophrenia: women vs men. Acta Psychiatr Scand. 1986 Jun; 73(6): 609-17.

[58] Childers SE, Harding CM. Gender, premorbid social functioning, and long-term outcome in DSM-III schizophrenia. Schizophrenia

bulletin. 1990; 16(2): 309-18. [59] McGrath JJ, Susser ES. New directions in the epidemiology of

schizophrenia. Med J Aust. 2009 Feb 16; 190(4 Suppl): S7-9. [60] Gur RE, Kohler CG, Ragland JD, Siegel SJ, Lesko K, Bilker WB,

et al. Flat affect in schizophrenia: relation to emotion processing and neurocognitive measures. Schizophr Bull. 2006 Apr; 32(2):

279-87. [61] Moriarty PJ, Lieber D, Bennett A, White L, Parrella M, Harvey

PD, et al. Gender differences in poor outcome patients with life-long schizophrenia. Schizophr Bull. 2001; 27(1): 103-13.

[62] Shtasel DL, Gur RE, Gallacher F, Heimberg C, Gur RC. Gender differences in the clinical expression of schizophrenia. Schizophr

Res. 1992 Sep; 7(3): 225-31. [63] Gur RE, Petty RG, Turetsky BI, Gur RC. Schizophrenia throughout

life: sex differences in severity and profile of symptoms. Schizophr Res. 1996 Jul; 21(1): 1-12.

[64] Goldstein JM, Seidman LJ, Goodman JM, Koren D, Lee H, Wein-traub S, et al. Are there sex differences in neuropsychological func-

tions among patients with schizophrenia? Am J Psychiatry. 1998 Oct; 155(10): 1358-64.

[65] Grossman LS, Harrow M, Rosen C, Faull R, Strauss GP. Sex dif-ferences in schizophrenia and other psychotic disorders: a 20-year

longitudinal study of psychosis and recovery. Compr Psychiatry. 2008 Nov-Dec; 49(6): 523-9.

[66] Ciompi L. Catamnestic long-term study on the course of life and aging of schizophrenics. Schizophrenia bulletin. 1980; 6(4): 606-

18. [67] Vaillant GE. The prediction of recovery in schizophrenia. J Nerv

Ment Dis. 1962 Dec; 135: 534-43. [68] Vaillant GE. Prospective Prediction of Schizophrenic Remission.

Arch Gen Psychiatry. 1964 Nov; 11: 509-18. [69] Stephens JH, Astrup C, Mangrum JC. Prognostic factors in recov-

ered and deteriorated schizophrenics. Am J Psychiatry. 1966 Apr; 122(10): 1116-21.

[70] Hubschmid T, Ciompi L.[Predictors of the course of schizophrenia--a review of the literature]. Fortschr Neurol Psychiatr. 1990 Oct;

58(10): 359-66. [71] Mouridsen SE, Hauschild KM. A longitudinal study of schizophre-

nia- and affective spectrum disorders in individuals diagnosed with a developmental language disorder as children. J Neural Transm.

2008 Nov; 115(11): 1591-7. [72] Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, et

al. Comorbidity of mental disorders with alcohol and other drug

abuse. Results from the Epidemiologic Catchment Area (ECA)

Study. JAMA. 1990 Nov 21; 264(19): 2511-8. [73] Lynskey M, White V, Hill D, Letcher T, Hall W. Prevalence of

illicit drug use among youth: results from the Australian School Students' Alcohol and Drugs Survey. Aust N Z J Public Health.

1999 Oct; 23(5): 519-24. [74] Smith FP. A discussion of "Method comparison of EMIT II and

OnLine with RIA for drug screening," (J. Forensic Sci., Vol. 38, No. 6, Nov. 1993, pp. 1326-1341). J Forensic Sci. 1994 Jul; 39(4):

909-11. [75] Arendt M, Rosenberg R, Foldager L, Perto G, Munk-Jorgensen P.

Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Br J

Psychiatry. 2005 Dec; 187: 510-5. [76] Arseneault L, Cannon M, Witton J, Murray RM. Causal association

between cannabis and psychosis: examination of the evidence. Br J Psychiatry. 2004 Feb; 184: 110-7.

[77] Macleod J, Davey Smith G, Hickman M. Does cannabis use cause schizophrenia? Lancet. 2006 Apr 1; 367(9516): 1055.

[78] Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish

conscripts of 1969: historical cohort study. BMJ. 2002 Nov 23; 325(7374): 1199.

[79] Dixon L, Haas G, Weiden P, Sweeney J, Frances A. Acute effects of drug abuse in schizophrenic patients: clinical observations and

patients' self-reports. Schizophr Bull. 1990; 16(1): 69-79. [80] Zammit S, Rasmussen F, Farahmand B, Gunnell D, Lewis G,

Tynelius P, et al. Height and body mass index in young adulthood and risk of schizophrenia: a longitudinal study of 1 347 520 Swed-

ish men. Acta Psychiatr Scand. 2007 Nov; 116(5): 378-85. [81] Goldstein JM, Buka SL, Seidman LJ, Tsuang MT. Specificity of

familial transmission of schizophrenia psychosis spectrum and af-fective psychoses in the New England family study's high-risk de-

sign. Arch Gen Psychiatry. May; 67(5): 458-67. [82] Mortensen PB, Pedersen MG, Pedersen CB. Psychiatric family

history and schizophrenia risk in Denmark: which mental disorders are relevant? Psychol Med. Feb; 40(2): 201-10.

[83] Laursen TM, Munk-Olsen T, Nordentoft M, Bo Mortensen P. A comparison of selected risk factors for unipolar depressive disor-

der, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a danish population-based cohort. J Clin Psy-

chiatry. 2007 Nov; 68(11): 1673-81. [84] Haukka JK, Suvisaari J, Lonnqvist J. Family structure and risk

factors for schizophrenia: case-sibling study. BMC Psychiatry. 2004; 4: 41.

[85] Lang UE, Puls I, Muller DJ, Strutz-Seebohm N, Gallinat J. Mo-lecular mechanisms of schizophrenia. Cell Physiol Biochem. 2007;

20(6): 687-702. [86] Brans RG, van Haren NE, van Baal GC, Schnack HG, Kahn RS,

Hulshoff Pol HE. Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia. Arch Gen Psychiatry.

2008 Nov; 65(11): 1259-68. [87] Spaniel F, Tintera J, Hajek T, Horacek J, Dezortova M, Hajek M, et

al. Language lateralization in monozygotic twins discordant and concordant for schizophrenia. A functional MRI pilot study. Eur

Psychiatry. 2007 Jul; 22(5): 319-22. [88] Simons CJ, Jacobs N, Jolles J, van Os J, Krabbendam L. Subclini-

cal psychotic experiences and cognitive functioning as a bivariate phenotype for genetic studies in the general population. Schizophr

Res. 2007 May; 92(1-3): 24-31. [89] Esterberg ML, Trotman HD, Holtzman C, Compton MT, Walker

EF. The impact of a family history of psychosis on age-at-onset and positive and negative symptoms of schizophrenia: a meta-analysis.

Schizophr Res. 2010 Jul; 120(1-3): 121-30. [90] Kee KS, Green MF, Mintz J, Brekke JS. Is emotion processing a

predictor of functional outcome in schizophrenia? Schizophr Bull. 2003; 29(3): 487-97.

[91] Antonovsky H, Sagy S. The development of a sense of coherence and its impact on responses to stress situations. J Soc Psychol. 1986

Apr; 126(2): 213-25. [92] Suddendorf T. Behavior. Foresight and evolution of the human

mind. Science. 2006 May 19; 312(5776): 1006-7. [93] Heijn C. On foresight. Psychoanal Study Child. 2005; 60: 312-34.

Longitudinal Course of Schizophrenia Current Psychiatry Reviews, 2011, Vol. 7, No. 3 11

[94] Eack SM, George MM, Prasad KM, Keshavan MS. Neuroanatomi-

cal substrates of foresight in schizophrenia. Schizophr Res. 2008 Aug; 103(1-3): 62-70.

[95] Eack SM, Keshavan MS. Foresight in schizophrenia: a potentially unique and relevant factor to functional disability. Psychiatr Serv.

2008 Mar; 59(3): 256-60. [96] Mesholam-Gately RI, Giuliano AJ, Goff KP, Faraone SV, Seidman

LJ. Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology. 2009 May; 23(3): 315-36.

[97] Jahshan C, Heaton RK, Golshan S, Cadenhead KS. Course of neu-rocognitive deficits in the prodrome and first episode of schizo-

phrenia. Neuropsychology. 2010 Jan; 24(1): 109-20. [98] Friedman JI, Harvey PD, Coleman T, Moriarty PJ, Bowie C, Par-

rella M, et al. Six-year follow-up study of cognitive and functional status across the lifespan in schizophrenia: a comparison with Alz-

heimer's disease and normal aging. Am J Psychiatry. 2001 Sep; 158(9): 1441-8.

[99] Lysaker PH, Dimaggio G, Carcione A, Procacci M, Buck KD, Davis LW, et al. Metacognition and schizophrenia: The capacity

for self-reflectivity as a predictor for prospective assessments of work performance over six months. Schizophr Res. 2009 May 18.

[100] Leeson VC, Barnes TR, Hutton SB, Ron MA, Joyce EM. IQ as a predictor of functional outcome in schizophrenia: a longitudinal,

four-year study of first-episode psychosis. Schizophr Res. 2009 Jan; 107(1): 55-60.

[101] van Winkel R, Myin-Germeys I, Delespaul P, Peuskens J, De Hert M, van Os J. Premorbid IQ as a predictor for the course of IQ in

first onset patients with schizophrenia: a 10-year follow-up study. Schizophr Res. 2006 Dec; 88(1-3): 47-54.

[102] Szoke A, Trandafir A, Dupont ME, Meary A, Schurhoff F, Leboyer M. Longitudinal studies of cognition in schizophrenia: meta-

analysis. Br J Psychiatry. 2008 Apr; 192(4): 248-57. [103] Ritsner M, Gibel A, Ratner Y. Determinants of changes in per-

ceived quality of life in the course of schizophrenia. Qual Life Res. 2006 Apr; 15(3): 515-26.

[104] Andreasen NC, Olsen S. Negative v positive schizophrenia. Defini-tion and validation. Arch Gen Psychiatry. 1982 Jul; 39(7): 789-94.

[105] Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry. 1982 Jul; 39(7): 784-8.

[106] Crow TJ. The two-syndrome concept: origins and current status. Schizophr Bull. 1985; 11(3): 471-86.

[107] Carpenter WT, Jr. The deficit syndrome. Am J Psychiatry. 1994 Mar; 151(3): 327-9.

[108] Husted JA, Beiser M, Iacono WG. Negative symptoms and the early course of schizophrenia. Psychiatry Res. 1992 Sep; 43(3):

215-22. [109] Bottlender R, Sato T, Groll C, Jager M, Kunze I, Moller HJ. Nega-

tive symptoms in depressed and schizophrenic patients: how do they differ? J Clin Psychiatry. 2003 Aug; 64(8): 954-8.

[110] Malla AK, Norman RM, Takhar J, Manchanda R, Townsend L, Scholten D, et al. Can patients at risk for persistent negative symp-

toms be identified during their first episode of psychosis? J Nerv Ment Dis. 2004 Jul; 192(7): 455-63.

[111] Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl. 2000; 401: 3-38.

[112] Taylor R, Langdon, R. . Understanding gender differences in schizophrenia: a review of the literature. Curr Psychiatr Rev.

2006(2): 255–65. [113] Bobes J, Arango C, Garcia-Garcia M, Rejas J. Prevalence of nega-

tive symptoms in outpatients with schizophrenia spectrum disor-ders treated with antipsychotics in routine clinical practice: findings

from the CLAMORS study. J Clin Psychiatry. 2010 Mar; 71(3): 280-6.

[114] Moller HJ, Jager M, Riedel M, Obermeier M, Strauss A, Bottlender R. The Munich 15-year follow-up study (MUFSSAD) on first-

hospitalized patients with schizophrenic or affective disorders: As-sessing courses, types and time stability of diagnostic classification.

Eur Psychiatry. 2010 Jul 9. [115] Moller HJ, Jager M, Riedel M, Obermeier M, Strauss A, Bottlender

R. The Munich 15-year follow-up study (MUFUSSAD) on first-hospitalized patients with schizophrenic or affective disorders:

comparison of psychopathological and psychosocial course and outcome and prediction of chronicity. Eur Arch Psychiatry Clin

Neurosci. 2010 Aug; 260(5): 367-84.

[116] Putnam KM, Harvey PD, Parrella M, White L, Kincaid M, Pow-

chik P, et al. Symptom stability in geriatric chronic schizophrenic inpatients: a one-year follow-up study. Biol Psychiatry. 1996 Jan

15; 39(2): 92-9. [117] McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise

overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008; 30: 67-76.

[118] McGrath JJ. Myths and plain truths about schizophrenia epidemi-ology--the NAPE lecture 2004. Acta Psychiatr Scand. 2005 Jan;

111(1): 4-11. [119] Pedersen CB, Mortensen PB. Why factors rooted in the family may

solely explain the urban-rural differences in schizophrenia risk es-timates. Epidemiol Psichiatr Soc. 2006 Oct-Dec; 15(4): 247-51.

[120] Weiser M, Werbeloff N, Vishna T, Yoffe R, Lubin G, Shmush-kevitch M, et al. Elaboration on immigration and risk for schizo-

phrenia. Psychol Med. 2008 Aug; 38(8): 1113-9. [121] Dealberto MJ. Ethnic origin and increased risk for schizophrenia in

immigrants to countries of recent and longstanding immigration. Acta Psychiatr Scand. May; 121(5): 325-39.

[122] McGrath JJ, Welham JL. Season of birth and schizophrenia: a systematic review and meta-analysis of data from the Southern

Hemisphere. Schizophr Res. 1999 Feb 15; 35(3): 237-42. [123] Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonal birth pat-

terns of neurological disorders. Neuroepidemiology. 2000 Jul-Aug; 19(4): 177-85.

[124] Wynn Owen PA, Castle DJ. Late-onset schizophrenia: epidemiol-ogy, diagnosis, management and outcomes. Drugs Aging. 1999

Aug; 15(2): 81-9. [125] McGorry PD, McKenzie D, Jackson HJ, Waddell F, Curry C. Can

we improve the diagnostic efficiency and predictive power of pro-dromal symptoms for schizophrenia? Schizophr Res. 2000 Apr 7;

42(2): 91-100. [126] McWalter H. Outcomes of treatment of schizophrenia in a North-

East Scottish mental hospital. American Journal of Psychiatry. 1961; 118: 529-33.

[127] Torgalsboen AK, Rund BR. "Full recovery" from schizophrenia in the long term: a ten-year follow-up of eight former schizophrenic

patients. Psychiatry. 1998 Spring; 61(1): 20-34. [128] Preti A, Cella M. Randomized-controlled trials in people at ultra

high risk of psychosis: a review of treatment effectiveness. Schizophr Res. 2010 Oct; 123(1): 30-6.

[129] Wyatt RJ, Damiani LM, Henter ID. First-episode schizophrenia. Early intervention and medication discontinuation in the context of

course and treatment. Br J Psychiatry Suppl. 1998; 172(33): 77-83. [130] Bola JR, Mosher LR. At issue: predicting drug-free treatment re-

sponse in acute psychosis from the Soteria project. Schizophr Bull. 2002; 28(4): 559-75.

[131] Bola JR, Mosher LR. Treatment of acute psychosis without neuro-leptics: two-year outcomes from the Soteria project. J Nerv Ment

Dis. 2003 Apr; 191(4): 219-29. [132] Ciompi L, Dauwalder HP, Maier C, Aebi E, Trutsch K, Kupper Z,

et al. The pilot project 'Soteria Berne'. Clinical experiences and re-sults. Br J Psychiatry Suppl. 1992 Oct(18): 145-53.

[133] Koshland DE, Jr. Philosophy of science. The Cha-Cha-Cha Theory of Scientific Discovery. Science. 2007 Aug 10; 317(5839): 761-2.

[134] Fink M, Taylor MA. The catatonia syndrome: forgotten but not gone. Arch Gen Psychiatry. 2009 Nov; 66(11): 1173-7.

[135] Bota RG, Munro JS, Sagduyu K. Benefits of boarding home placement in patients with schizophrenia. South Med J. 2007 Feb;

100(2): 145-8. [136] Stephens JH, Astrup C, Carpenter WT, Jr., Shaffer JW, Goldberg J.

A comparison of nine systems to diagnose schizophrenia. Psychia-try Res. 1982 Apr; 6(2): 127-43.

[137] Ciompi L, Medvecka J.[Comparative study of long-term mortality in the mentally ill]. Schweiz Arch Neurol Neurochir Psychiatr.

1976; 118(1): 111-35. [138] Strauss GP, Harrow M, Grossman LS, Rosen C. Periods of Recov-

ery in Deficit Syndrome Schizophrenia: A 20-Year Multi-follow-up Longitudinal Study. Schizophr Bull. 2008 Dec 18.

[139] Stephens JH. Long-term prognosis and followup in schizophrenia. Schizophr Bull. 1978; 4(1): 25-47.

[140] Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull. 1991; 17(2): 325-51.

[141] Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients

12 Current Psychiatry Reviews, 2011, Vol. 7, No. 3 Bota and Preda

with schizophrenia, second edition. The American journal of psy-

chiatry. 2004 Feb; 161(2 Suppl): 1-56. [142] Agency for Health Technology Assessment and Research

WGotCPGfSaIPD, Mental Health Forum c. Clinical Practice Guideline for Schizophrenia and Incipient Psychotic Disorder.

Quality Plan for the National Health System of the Ministry of Health and Consumer Affairs 2009; 2006/05-2.

[143] Fenton WS, McGlashan TH. Prognostic scale for chronic schizo-

phrenia. Schizophrenia bulletin. 1987; 13(2): 277-86. [144] Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geis-

ler S, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Archives of

general psychiatry. 1999 Mar; 56(3): 241-7.

Received: 00 00, 2011 Revised: 00 00, 2011 Accepted: 00 00, 2011