Abstract

Psychiatric comorbidities are common among patients with schizophrenia. Substance abuse comorbidity predominates. Anxiety and depressive symptoms are also very common throughout the course of illness, with an estimated prevalence of 15% for panic disorder, 29% for posttraumatic stress disorder, and 23% for obsessive-compulsive disorder. It is estimated that comorbid depression occurs in 50% of patients, and perhaps (conservatively) 47% of patients also have a lifetime diagnosis of comorbid substance abuse. This article chronicles these associations, examining whether these comorbidities are “more than chance” and might represent (distinct) phenotypes of schizophrenia. Among the anxiety disorders, the evidence at present is most abundant for an association with obsessive-compulsive disorder. Additional studies in newly diagnosed antipsychotic-naive patients and their first-degree relatives and searches for genetic and environmental risk factors are needed to replicate preliminary findings and further investigate these associations.

The clinical heterogeneity of schizophrenia is indisputable. Virtually no 2 patients present with the same constellation of symptoms. Moreover, even in the same patient, symptoms can show dramatic change over time, and there is significant interplay between different sets of symptoms: eg, “secondary” negative symptoms might be ameliorated with resolution of positive symptoms, while core “deficit” negative symptoms are more enduring but can worsen over the longitudinal course of illness. Such observations give way to considerations that these may even constitute groups of diseases of generally common phenotypic expression but of different underlying etiopathology.1

Further complicating the clinical picture of schizophrenia as well as understanding the boundaries and etiology of this condition is the substantial psychiatric comorbidity.2 Depression, anxiety, and substance abuse are common accompaniments of the schizophrenia condition, and they in turn perturb the clinical picture.3 For example, depression can cause secondary negative symptoms, panic attacks can drive paranoia, and cannabis abuse can worsen positive and disorganization symptoms. Conversely, depressive symptoms seen in the context of a florid psychotic relapse often resolve with treatment of the positive symptoms but may remerge in the “postpsychotic” state and in turn worsen the longitudinal course of the illness.4,5

Nosologists have great difficulty dealing with complex sets of symptoms.3,6,7 Generally, an implicit or explicit hierarchy is embraced, such that schizophrenia “trumps,” depression, and anxiety. Or, if no primacy can be determined, resort is made to labels such as “schizoaffective disorder” or even “schizoobsessive” subtype of schizophrenia.3,8 An alternative approach, reified in Diagnostic and Statistical Manual of Mental Disorders, is to consider these symptoms as part of another axis I diagnosis that is occurring alongside schizophrenia.9 Under this scenario, the patient has 2 major conditions, and these have co-occurred (perhaps for some etiological reason common to both disorders). This is very much the model considered—and clinically endorsed—when a patient with schizophrenia also has an alcohol dependence or drug addiction problem.10 Additionally, recent work on the potential biological vulnerability to cannabis abuse that might explain some variance in the risk of later developing schizophrenia raises again the proposition that the clinical associations that we commonly observe in schizophrenia may also have biological and potentially etiopathological significance. 11

Bermanzohn et al12 provocatively proposed that we “stake out the midground”; they suggest that psychiatric comorbidities are so common that they might be integral to schizophrenia. To a large extent, our current research in clinical trials and neurobiological studies is increasingly coming in line with this proposition because now such studies support broad inclusion criteria of “all comers” … the schizophrenia patients whom we see in everyday clinical practice, who have prominent anxiety symptoms, or may also have depressive symptoms, and also abuse drugs and alcohol.

The purpose of this article is to “take stock” of these (anxiety, depression, and substance abuse) comorbidities and their relationship to schizophrenia. Reviewing the relevant epidemiological, genetic/familial, neurobiological, and therapeutic literature, we ask whether comorbidities should be considered:

  • to have simply, by chance, co-occurred with schizophrenia;

  • to have manifested “secondary” to the core disorder, schizophrenia;

  • to have manifested because schizophrenia is more common in this core disorder; or

  • are a consequence of some underlying shared liability to both sets of disorders.

Schizophrenia and Anxiety

There is an increased prevalence of anxiety disorders among patients with schizophrenia compared with the general population.13 These include panic disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), generalized anxiety disorder, and social anxiety disorder. Prevalence estimates are influenced by heterogeneity among definitions of symptoms and rating instruments used for diagnosis. Other diagnostic issues complicating the study of anxiety in schizophrenia are that symptoms may occur spontaneously, intermittently, in direct response to psychotic symptoms, and/or as a side effect of antipsychotic medications. Here, we will focus on panic disorder, PTSD, and OCD, the 3 anxiety disorders that have been most extensively studied in patients with schizophrenia.

Panic Attacks and Panic Disorder

Two studies from the National Institute of Mental Health Epidemiologic Catchment Area survey found a 28%–63% (across the 5 study sites)14 and 45%15 prevalence, respectively, of panic attacks in patients with schizophrenia. Two other studies from the ECA survey16,17 found a lifetime odds of ≥35 for having panic disorder in subjects with (compared with those without) a diagnosis of schizophrenia. In total, 27 published studies have investigated the epidemiology of panic symptoms among patients with schizophrenia.12,14–39 (see Table 1) The prevalence of panic attacks (7.1%–63%) and panic disorder (3.3%–29.5%) vary widely across these studies. A weighted average of the available data from these (heterogeneous) studies crudely estimates a 25% prevalence of panic attacks and a 15% prevalence of panic disorder in patients with schizophrenia (data not shown). By comparison, the lifetime prevalence of panic disorder in the US general population ranges from 2.0%–5.1%.17,40,41

Table 1.

Prevalence of Panic Attacks and Panic Disorder in Schizophrenia

Study Sample Criteria Prevalence Notes 
Boyd et al16 Epidemiological Catchment Area DSM-III/DIS  OR=37.9  
Robin and Regier17 Epidemiological Catchment Area DSM-III/DIS  OR=35  
Tien and Eaton42 Epidemiological Catchment Area DSM-III/DIS 40 OR=2.28 Attacks 
Boyd14 Epidemiological Catchment Area DSM-III/DIS  28-63% Attacks 
Bland et al20 Random community sample DSM-III 20 29.5%  
Argyle18 Outpatients DSM-III-R 20 35% Attacks 
    20% Disorder 
Lyons et al32 Affected co-twins  24 12.5%  
Moorey and Soni33 Outpatients DSM-III-R 30 17% Attacks 
Cassano et al21 Inpatients (consecutive) DSM-III-R/SCID-P 31 19.4%  
Chen et al22 Outpatients SCID DSM-IV 32 25% Attacks 
Tibbo et al36 Outpatients MINI DSM-IV 32 3.3%  
Bermanzohn et al12 Day hospital (consecutive) SCID DSM-IV 37 10.8%  
Bayle et al. (2001) Outpatients DSM-III-R 40 36.8% Attacks 
Ciapparelli et al23 1-year cohort of patients in remission DSM-IV 42 26.2%  
Cutler and Siris26 Outpatients (primarily) with post-psychotic depression RDC 45 24.4%  
Labbate et al31 Inpatients (consecutive, veterans) DSM-IV 49 43% Attacks 
    33% Disorder 
Ulas et al37  Bandelow Panic and 49 31% Attacks 
  Agoraphobia Rating Scale  14% Disorder 
Braga et al39 Outpatients SCID DSM-IV 53 5.7%  
Zarate38 Outpatients (random sample) DSM-IV 60 19.4%  
Cosoff and Hafner25 Inpatients (consecutive) SCID DSM-III-R 60 6.3%  
Higuchi et al30 Outpatients SCID DSM-III-R 45 20%  
Pallanti et al34 Outpatients SCID DSM-IV 80 13.8%  
Heun and Maier29 Family study DSM-III-R 88 33%  
Garvey et al27 Inpatients DSM-III 95 17%  
Strakowski et al35 Inpatients with first-episode psychosis SCID DSM-III-R 102 6%  
Goodwin et al28 Inpatients DIGS DSM-III-R 184 7.1% Attacks 
Craig et al24 Inpatients with first-episode psychosis SCID DSM-III-R 225 10-20% Symptoms 
Goodwin et al15 Epidemiological Catchment Area DSM-III/DIS 260 45% Attacks 
Study Sample Criteria Prevalence Notes 
Boyd et al16 Epidemiological Catchment Area DSM-III/DIS  OR=37.9  
Robin and Regier17 Epidemiological Catchment Area DSM-III/DIS  OR=35  
Tien and Eaton42 Epidemiological Catchment Area DSM-III/DIS 40 OR=2.28 Attacks 
Boyd14 Epidemiological Catchment Area DSM-III/DIS  28-63% Attacks 
Bland et al20 Random community sample DSM-III 20 29.5%  
Argyle18 Outpatients DSM-III-R 20 35% Attacks 
    20% Disorder 
Lyons et al32 Affected co-twins  24 12.5%  
Moorey and Soni33 Outpatients DSM-III-R 30 17% Attacks 
Cassano et al21 Inpatients (consecutive) DSM-III-R/SCID-P 31 19.4%  
Chen et al22 Outpatients SCID DSM-IV 32 25% Attacks 
Tibbo et al36 Outpatients MINI DSM-IV 32 3.3%  
Bermanzohn et al12 Day hospital (consecutive) SCID DSM-IV 37 10.8%  
Bayle et al. (2001) Outpatients DSM-III-R 40 36.8% Attacks 
Ciapparelli et al23 1-year cohort of patients in remission DSM-IV 42 26.2%  
Cutler and Siris26 Outpatients (primarily) with post-psychotic depression RDC 45 24.4%  
Labbate et al31 Inpatients (consecutive, veterans) DSM-IV 49 43% Attacks 
    33% Disorder 
Ulas et al37  Bandelow Panic and 49 31% Attacks 
  Agoraphobia Rating Scale  14% Disorder 
Braga et al39 Outpatients SCID DSM-IV 53 5.7%  
Zarate38 Outpatients (random sample) DSM-IV 60 19.4%  
Cosoff and Hafner25 Inpatients (consecutive) SCID DSM-III-R 60 6.3%  
Higuchi et al30 Outpatients SCID DSM-III-R 45 20%  
Pallanti et al34 Outpatients SCID DSM-IV 80 13.8%  
Heun and Maier29 Family study DSM-III-R 88 33%  
Garvey et al27 Inpatients DSM-III 95 17%  
Strakowski et al35 Inpatients with first-episode psychosis SCID DSM-III-R 102 6%  
Goodwin et al28 Inpatients DIGS DSM-III-R 184 7.1% Attacks 
Craig et al24 Inpatients with first-episode psychosis SCID DSM-III-R 225 10-20% Symptoms 
Goodwin et al15 Epidemiological Catchment Area DSM-III/DIS 260 45% Attacks 

DIGS = Diagnostic Interview for Genetic Studies RDC = Research Diagnostic Criteria

DIS = Diagnostic Interview Schedule SCID-P = Structured Clinical Interview for DSM-Patient Version

MINI = Mini International Neuropsychiatric Interview

The majority of studies of panic attacks/disorder focused on patients with chronic schizophrenia. Two studies, however, investigated the prevalence of panic symptoms in patients with first-episode psychosis (FEP), which reduces confounding by medications and other factors. Strakowski et al35 found that of 102 consecutive patients hospitalized FEP patients, 6% met Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria for panic disorder. The authors also found poorer initial outcomes in patients with comorbid panic disorder. In another study, Craig et al24 examined panic symptoms in 225 patients with first-admission psychosis (schizophrenia or schizoaffective disorder) participating in the Suffolk County (NY) Mental Health Project. Panic symptoms were present at baseline in 11.2% of patients. Furthermore, patients with baseline panic symptoms were significantly more likely to exhibit positive symptoms of psychosis after 24 months.

Evidence from 3 studies18,19,31 suggests that panic symptoms may be more common in patients with paranoid schizophrenia, compared with other schizophrenia subtypes or schizoaffective disorder. Furthermore, panic attacks were frequently related to paranoid ideations in these studies. Bermanzohn et al43 described the potential for a relationship between panic attacks to paranoia. Comorbid panic symptoms may be associated with more severe psychopathology,22,23,30,36,37 as well as increased risks of suicidal ideation and behavior,26,45,46 and may also increase vulnerability to comorbid substance use.28

In a contrasting approach to the epidemiology of this association, another study from the ECA survey by Tien and Eaton42 found that the presence of panic attacks was associated with a 2.28-fold increased risk of developing schizophrenia. The temporality of this association suggests that, for some patients, the presence of panic attacks may be part of the psychosis prodrome.

Weissman et al47 reported on a potential syndrome with genetic linkage to chromosome 13q32 (marker D13S779) in 34 families segregating for panic disorder. In addition to panic disorder, these patients also had an excess of urologic problems, headaches, thyroid problems, and/or mitral valve prolapse. This region of chromosome 13 (13q32–34) encodes the G72/G30 gene complex (G72 is also known as D-amino acid oxidase activator or DAOA), which has been linked to schizophrenia in multiple studies, as reviewed in a recent meta-analysis.48 Additional studies are needed to investigate potential shared genetic risk factors for schizophrenia and panic disorder.

Family and twin studies support the biological plausibility of an association between schizophrenia and panic disorder. Heun and Maier29 reported on the only family study of panic disorder in schizophrenia. They assessed a total of 1068 first-degree relatives of 59 patients with schizophrenia, 54 patients with panic disorder, 29 patients with panic disorder and schizophrenia, and 109 controls. They found a significantly increased prevalence of primary panic disorders among relatives of patients with schizophrenia (4.3%) compared with controls (0.9%) but not compared with subjects with panic disorder. Furthermore, there was not an increased risk of schizophrenia among relatives of patients with either panic disorder (0%) or control subjects (0.3%). In a sample of N = 24 twin pairs discordant for schizophrenia and N = 3327 twins without schizophrenia from the Vietnam Era Twin Registry, Lyons et al32 found that the nonaffected co-twins of schizophrenia probands had a 3-fold increased odds of panic disorder compared with control twins. This finding did not reach statistical significance, but the results were limited by the small sample size of the study.

One large family study found an increased prevalence of panic disorder in first-degree relatives of patients with schizophrenia. However, the present evidence supporting the hypothesis that panic disorder is part of the syndrome of schizophrenia is limited, subject to confounding, and findings are in need of replication. Additional studies in drug-naive patients and their first-degree relatives, controlling for potential confounding factors are also needed to further investigate this association. Twin studies might also contribute to our knowledge base in this regard.

Posttraumatic Stress Disorder

Trauma histories are common in patients with schizophrenia, and childhood trauma is a risk factor for psychosis.49 Patients with schizophrenia may be at increased risk for exposure to trauma, due to illness-related features, environmental influences, and/or comorbid substance use. Many factors complicate the diagnosis and investigation of co-occurring PTSD and schizophrenia, including the presence of psychotic symptoms within the context of PTSD, or PTSD symptoms—such as reexperiencing the trauma—that may mimic psychotic symptoms. Furthermore, psychotic symptoms (eg, hallucinations and delusions) or experiences (eg, involuntary hospitalization, seclusion, restraint, forced medications) may themselves be a traumatic event contributing to PTSD,50–54 though they have not been uniformly considered as a potential precipitating stressor.

A total of 20 published studies have reported on the epidemiology of PTSD in schizophrenia. 32,34,36,39,51–66 (see Table 2) These samples, including those which considered psychosis-related symptoms or experiences, found a prevalence of PTSD among patients with psychosis 0%–67%. A weighted average of the available data from these (heterogeneous) studies crudely estimates a 29% prevalence of PTSD in patients with schizophrenia, compared with a 7.8% estimated lifetime prevalence of PTSD in the US general population.67

Table 2.

Prevalence of Post-Traumatic Stress Disorder in Schizophrenia

Study Sample Criteria Prevalence Notes 
Strakowski et al66 First-episode psychosis SCID DSM-III-R 18 22%  
Lyons et al32 Affected co-twins  24 16.7%  
Kennedy et al51 Outpatients DSM-IV/Penn PTSD Inventory 30 23.3%  
Kilcommons and Morrison58 Outpatient sample of convenience DSM-IV 32 53%  
Tibbo et al36 Outpatients MINI DSM-IV 32 0%  
McGorry et al. (2001) Inpatients followed for one year DSM-III 36 46%
35% 
At 4 months
At 11 months 
Shaw et al. (1997) Inpatients CIDI/CAPS 42 52.4%  
Meyer et al. (1999) Inpatients CAPS 46 11%  
Resnick et al. (2003) Outpatients CAPS 47 13%  
Braga et al39 Outpatients SCID DSM-IV 53 3.8%  
Gearon et al. (2003) Outpatient females, comorbid substance use disorder DSM-IV 54 46%  
Frame & Morrison (2001) Inpatients DSM-IV/
Davidson checklist 
60 67% At discharge 
Seedat et al65 Inpatients MINI 70 4.3%  
Pallanti et al34 Outpatients SCID DSM-IV 80 1.3%  
Fan et al. (2008) Outpatients DSM-IV 87 17% All with trauma history 
Mueser et al. (1998) Multicenter inpatients and outpatients Chart records 94 30.9%  
Priebe et al. (1998) Outpatients DSM-III-R 105 51%  
Calhoun et al. (2007) Inpatient male veterans SCID/PTSD checklist 165 47%  
Neria et al. (2002) Inpatients with first-episode psychosis DSM-III-R 170 10.0%  
Mueser et al. (2004) Multicenter inpatients and outpatients PTSD checklist 526 31.6%  
Study Sample Criteria Prevalence Notes 
Strakowski et al66 First-episode psychosis SCID DSM-III-R 18 22%  
Lyons et al32 Affected co-twins  24 16.7%  
Kennedy et al51 Outpatients DSM-IV/Penn PTSD Inventory 30 23.3%  
Kilcommons and Morrison58 Outpatient sample of convenience DSM-IV 32 53%  
Tibbo et al36 Outpatients MINI DSM-IV 32 0%  
McGorry et al. (2001) Inpatients followed for one year DSM-III 36 46%
35% 
At 4 months
At 11 months 
Shaw et al. (1997) Inpatients CIDI/CAPS 42 52.4%  
Meyer et al. (1999) Inpatients CAPS 46 11%  
Resnick et al. (2003) Outpatients CAPS 47 13%  
Braga et al39 Outpatients SCID DSM-IV 53 3.8%  
Gearon et al. (2003) Outpatient females, comorbid substance use disorder DSM-IV 54 46%  
Frame & Morrison (2001) Inpatients DSM-IV/
Davidson checklist 
60 67% At discharge 
Seedat et al65 Inpatients MINI 70 4.3%  
Pallanti et al34 Outpatients SCID DSM-IV 80 1.3%  
Fan et al. (2008) Outpatients DSM-IV 87 17% All with trauma history 
Mueser et al. (1998) Multicenter inpatients and outpatients Chart records 94 30.9%  
Priebe et al. (1998) Outpatients DSM-III-R 105 51%  
Calhoun et al. (2007) Inpatient male veterans SCID/PTSD checklist 165 47%  
Neria et al. (2002) Inpatients with first-episode psychosis DSM-III-R 170 10.0%  
Mueser et al. (2004) Multicenter inpatients and outpatients PTSD checklist 526 31.6%  

CAPS = Clinician-Administered PTSD Scale

CIDI = Composite International Diagnostic Interview

MINI = Mini International Neuropsychiatric Interview

While the majority of these studies focused on patients with chronic schizophrenia, Strakowski et al66 found that 4 of 18 (22%) patients with a schizophrenia-spectrum disorder met criteria for PTSD antecedent to their first psychotic episode. The diagnosis of PTSD predated the onset of the psychotic disorder by more than 1 year in 2 of these 4 patients. In a cohort of 170 patients with a FEP, Neria et al62 found a 10% prevalence of PTSD.

The presence of PTSD has also been shown to be associated with more severe psychopathology (including cognitive impairments)56,58,70,71, higher rates of suicidal ideation and suicidal behaviors,68 and more frequent outpatient physical health visits and hospitalizations69 in patients with schizophrenia.

Although a majority of studies found an increased prevalence of PTSD in excess of that in the general population, including inpatients with both FEP and chronic schizophrenia, there is little other evidence to support the hypothesis that PTSD is part of the illness of schizophrenia. The increased prevalence may be largely accounted for by environmental factors, particularly increased rates of exposure to childhood trauma or as the direct result of psychosis-related trauma. Factors, both clinical and neurobiological, that confer increased vulnerability to PTSD in patients with schizophrenia have been largely unexplored. We are aware of no published genetic or family studies of patients with schizophrenia and PTSD. In the twin study of Lyons et al,32 nonaffected monozygotic co-twins of schizophrenia probands had a nonsignificant increased odds of PTSD compared with control twins.

Obsessive-Compulsive Disorder

Obsessive-compulsive symptoms (OCS) and OCD have been frequently studied in patients with schizophrenia (see Table 3), with the majority showing an increased rate of both OCS and OCD in schizophrenia. A study from the ECA survey14 found a 12.5-fold increased odds of having OCD given a diagnosis of schizophrenia. By contrast, another study from this survey42 found a 3.77-fold increased risk of schizophrenia among patients with OCD, suggesting that, for some patients, the presence of OCD may be part of the psychosis prodrome. A total of 36 studies have investigated the epidemiology of OCS/OCD among patients with schizophrenia.12,15,16,19–21,23–25,28,34–36,38–40,65,66,72–87 (see Table 3) The prevalence of OCS (10%–64%) and OCD (0%–31.7%) vary widely across these studies and may have been overestimated due to difficulties in distinguishing clinically obsessions and delusions. It may be very difficult to determine whether the patient is experiencing an obsession or a delusion, especially when an obsession is held with firm conviction. A weighted average of the available data from these (heterogeneous) studies crudely estimates a 25% prevalence of OCS and a 23% prevalence of OCD in patients with schizophrenia. OCS are present throughout the course of schizophrenia. Several studies have suggested that OCS manifest as part of the psychosis prodrome. 88–91 Two studies72,91 found that the presence of OCS was associated wither earlier age of onset of psychosis. Additionally, 3 studies35,66,84 have found an 11.0%–15.2% prevalence of OCD in patients with FEP.

Table 3.

Prevalence of Obsessive-Compulsive Disorder in Schizophrenia

Study Sample Criteria Prevalence Notes 
Boyd et al16 Epidemiological Catchment Area DSM-III/DIS  OR=12.5  
Tien and Eaton42 Epidemiological Catchment Area DSM-III/DIS 40 OR=3.77  
Karno et al77 Epidemiological Catchment Area DSM-III/DIS  12.2%  
Rae (unpublished) Epidemiological Catchment Area reanalysis DSM-III/DIS  23.7%  
Mohammadi et al81 Community sample  12 OR=1.3 Symptoms 
Strakowski et al66 Inpatients with first-episode psychosis SCID DSM-III-R 18 11%  
Bland et al20 Random community sample DSM-III 20 59.2% Symptoms 
Cassano et al21 Inpatients (consecutive) DSM-III-R/SCID-P 31 29%  
Tibbo et al36 Outpatients MINI DSM-IV 32 0%  
Bermanzohn et al12 Day hospital (consecutive) SCID DSM-IV 37 29.7%  
Nechmad et al82 Inpatients DSM-IV 39 30.8% Adolescents 
Bayle et al. (2001) Outpatients DSM-III-R 40 35%  
Ciapparelli et al23 1-y cohort of patients in remission DSM-IV 42 23.8%  
Fabisch et al74  DSM-IV 42 19%  
Poyurovsky et al84 Inpatients with first-episode psychosis SCID 46 15.2% Adolescents 
Porto et al83 Day program SCID DSM-IV 50 60%, 26% Symptoms disorder 
Tibbo et al87 Outpatients SCID DISM-IV 52 25%  
Braga et al39 Outpatients SCID DSM-IV 53 15.1%  
Tibbo et al86 Outpatients SCID DISM-IV 56 25%  
Cosoff and Hafner25 Inpatients (consecutive) SCID DSM-III-R 60 13.8%  
Zarate38 Outpatients (random sample) DSM-IV 60 6.7%  
Poyurovsky et al85 Inpatients SCID DSM-IV 68 23.5%  
Seedat et al65 Inpatients MINI 70 4.3%  
Ohta et al. (2003) Inpatients and outpatients SCID DSM-IV 71 18.3%  
Kruger et al. (2000) Inpatients SCID DSM-III-R 76 15.8%  
Eisen et al73  SCID DSM-III-R 77 7.8%  
Pallanti et al34 Outpatients SCID DSM-IV 80 22.5%  
Kayahan et al78 Inpatients and outpatients SCID-P DSM-IV 100 64%, 30% Symptoms disorder 
Strakowski et al35 Inpatients with first-episode psychosis SCID DSM-III-R 102 13.7%  
Berman et al72 Outpatients Chart review 102 25% Symptoms 
Fabisch et al75 Inpatients DSM-IV 150 10% Symptoms 
Fenton and McGlashan76 Inpatients followed for 15 y DSM-III-R 163 12.9% Symptoms 
Goodwin et al28 Inpatients DIGS DSM-III-R 184 5.4%  
Craig et al24 Inpatients with first-episode psychosis SCID DSM-III-R 225 16.9%, 4% Symptoms disorder 
Meghani et al80 Outpatients Unspecified 1458 31.7%  
Study Sample Criteria Prevalence Notes 
Boyd et al16 Epidemiological Catchment Area DSM-III/DIS  OR=12.5  
Tien and Eaton42 Epidemiological Catchment Area DSM-III/DIS 40 OR=3.77  
Karno et al77 Epidemiological Catchment Area DSM-III/DIS  12.2%  
Rae (unpublished) Epidemiological Catchment Area reanalysis DSM-III/DIS  23.7%  
Mohammadi et al81 Community sample  12 OR=1.3 Symptoms 
Strakowski et al66 Inpatients with first-episode psychosis SCID DSM-III-R 18 11%  
Bland et al20 Random community sample DSM-III 20 59.2% Symptoms 
Cassano et al21 Inpatients (consecutive) DSM-III-R/SCID-P 31 29%  
Tibbo et al36 Outpatients MINI DSM-IV 32 0%  
Bermanzohn et al12 Day hospital (consecutive) SCID DSM-IV 37 29.7%  
Nechmad et al82 Inpatients DSM-IV 39 30.8% Adolescents 
Bayle et al. (2001) Outpatients DSM-III-R 40 35%  
Ciapparelli et al23 1-y cohort of patients in remission DSM-IV 42 23.8%  
Fabisch et al74  DSM-IV 42 19%  
Poyurovsky et al84 Inpatients with first-episode psychosis SCID 46 15.2% Adolescents 
Porto et al83 Day program SCID DSM-IV 50 60%, 26% Symptoms disorder 
Tibbo et al87 Outpatients SCID DISM-IV 52 25%  
Braga et al39 Outpatients SCID DSM-IV 53 15.1%  
Tibbo et al86 Outpatients SCID DISM-IV 56 25%  
Cosoff and Hafner25 Inpatients (consecutive) SCID DSM-III-R 60 13.8%  
Zarate38 Outpatients (random sample) DSM-IV 60 6.7%  
Poyurovsky et al85 Inpatients SCID DSM-IV 68 23.5%  
Seedat et al65 Inpatients MINI 70 4.3%  
Ohta et al. (2003) Inpatients and outpatients SCID DSM-IV 71 18.3%  
Kruger et al. (2000) Inpatients SCID DSM-III-R 76 15.8%  
Eisen et al73  SCID DSM-III-R 77 7.8%  
Pallanti et al34 Outpatients SCID DSM-IV 80 22.5%  
Kayahan et al78 Inpatients and outpatients SCID-P DSM-IV 100 64%, 30% Symptoms disorder 
Strakowski et al35 Inpatients with first-episode psychosis SCID DSM-III-R 102 13.7%  
Berman et al72 Outpatients Chart review 102 25% Symptoms 
Fabisch et al75 Inpatients DSM-IV 150 10% Symptoms 
Fenton and McGlashan76 Inpatients followed for 15 y DSM-III-R 163 12.9% Symptoms 
Goodwin et al28 Inpatients DIGS DSM-III-R 184 5.4%  
Craig et al24 Inpatients with first-episode psychosis SCID DSM-III-R 225 16.9%, 4% Symptoms disorder 
Meghani et al80 Outpatients Unspecified 1458 31.7%  

DIS = Diagnostic Interview Schedule SCID-P = Structured Clinical Interview for DSM-Patient Version

MINI = Mini International Neuropsychiatric Interview

Several studies have directly compared clinical features of schizophrenia with or without comorbid OCD. In a study of 22 adolescents with schizophrenia and OCD matched for age, gender, and number of hospitalizations with 22 adolescents with non-OCD schizophrenia, Poyurovsky et al91 found that patients with schizophrenia and OCD had earlier age of onset of illness and more OCD-spectrum disorders, including primary tic disorders. There was no difference in the severity of schizophrenia symptoms based on the presence or absence of OCD. In a majority of patients in this study, OCS either preceded or co-occurred with the onset of schizophrenia. Poyurovsky et al92 also compared 100 patients with schizophrenia and OCD, 100 patients with schizophrenia but no OCD, and 35 patients with OCD alone. They found an increased prevalence of OCD-spectrum disorders, including body dysmorphic disorder and tic disorder, among patients with schizophrenia and OCD vs non-OCD schizophrenia. There were no differences in affective, anxiety, and substance use disorders between these groups. The prevalence of OCD-spectrum disorders was similar between patients with schizophrenia and OCD and those with OCD. In a study of schizophrenia with and without OCD (n = 50 in each group), Rajkumar et al93 found that comorbid OCD was associated with greater paranoia and first-rank psychotic symptoms, less anergia, increased rates of depression and comorbid personality disorder, and perhaps less disability. Several studies have found more severe neuropsychological impairments in patients with schizophrenia and OCD.94,95 In comparison to patients with non-OCD schizophrenia and OCD, Whitney et al95 found that patients with schizophrenia and OCD had greater impairments across several domains of executive function.

The presence of OCD also has prognostic significance in patients with schizophrenia. Parenthetically, obsessive symptoms—as was the case with affective symptoms—were originally considered to be of favorable prognostic value. This does not appear to be the case. Braga et al39 found that patients with schizophrenia and comorbid OCD had greater disability as measured by Sheehan disability scale global scale, work subscale, and social life subscale scores. In a study of N = 102 patients with chronic schizophrenia, Berman et al72 found that the presence of OCS was associated with earlier age of illness onset, increased rates of hospitalization in the previous 5 years, and a decreased likelihood of being employed or married. Sevincok et al96 found that OCD was an independent risk factor for suicidal ideation and suicide attempts in patients with schizophrenia. OCD was also more prevalent among patients with (than those without) suicidal ideation. The authors also found that compulsions were a predictor of suicide attempts.

Poyurovsky et al.97 completed an important family study of schizophrenia probands with (n = 57) and without (n = 60) OCD and 50 controls. Relatives of probands with combined schizophrenia and OCD (n = 182) had significantly increased rates of schizophrenia and OCD, as well as obsessive-compulsive personality disorder, than probands with non-OCD schizophrenia (n = 210). There was also a trend for an increased risk of OCD in relatives of probands with schizophrenia and OCD compared wiith non-OCD schizophrenia. Furthermore, relatives of probands with schizophrenia did not differ in risk of schizophrenia-spectrum, mood, or substance use disorders, based on the presence or absence of OCD. The authors argued that the differential aggregation of obsessive-compulsive-spectrum disorders in first-degree relatives supports the validity of a putative “schizoobsessive” schizophrenia subtype. In the only published genetic study of patients with schizophrenia and OCD, Poyurovsky et al98 completed a case-control study of the COMT Val158 Met polymorphism. They found no differences in COMT allele and genotype distribution between patients with schizophrenia and OCD (n = 113), OCD (n = 79), and controls (n = 171).

Dopamine and serotonin are key neurotransmitters involved in the pathophysiology of both schizophrenia and OCD. While substantial overlap in neurobiology87,99 may well contribute to the association between these disorders, a potential confounding factor in epidemiological studies of this association is that second-generation antipsychotics (SGAs) with serotonergic 5HT2 receptor blockade may exacerbate or produce de novo OCS in patients with schizophrenia.100–103 By contrast, SGAs have also been effective as an adjunctive medication for treatment-refractory OCD.104–107 Additional studies are needed to this investigate the neurobiology of this paradox, which has important treatment-related implications.

Taken together, several lines of evidence suggest that patients with both schizophrenia and OCD may represent a “schizoobsessive” subtype of schizophrenia, with differences in psychopathology, course of illness, and response to treatment, as opposed to comorbid syndromes. This literature supports the possibility that, in a subgroup of patients, OCD may be part of the illness of schizophrenia. Further studies in large samples from diverse population, including in newly diagnosed antipsychotic-naive patients, designed to control for potential confounding factors, are needed to replicate preliminary findings. The search for shared environmental risk factors, such as low birth weight or prenatal stress, for schizophrenia and OCD represents another area for future investigation. The presence of such factors would not provide direct evidence for the relationship between these 2 conditions but would support the biological plausibility of their association. Additional family and genetic studies are needed to determine if schizophrenia and OCD constitute part of the heritable schizophrenia spectrum are accounted for by shared environmental risk factors or both.

Schizophrenia and Depression

The relationship between psychotic and affective symptoms has been central to the dilemma of psychiatric classification. Indeed, substantial evidence (not reviewed here) show that schizophrenia and bipolar disorder, in particular, may be distributed across a dimensional spectrum (or more apt, across multidimensional spectra).108–112 Furthermore, there has been an ongoing and robust debate about the nosological status of “schizoaffective” disorder,7,8,112 with varying definitions and approaches that make that literature very difficult to negotiate. These 2 aspects go way beyond the scope of this review yet are important aspects of nosology that are of relevance to the topic of psychiatric comorbidity. Here, we confine ourselves to reviewing studies of the co-occurrence of the symptoms of psychosis and unipolar depression, a phenomenon seen at some point in illness in the majority of schizophrenia sufferers, as well as in a substantial number of primary depressive patients. In this context, Möller poses the question: “whether these depressive symptoms are part of the rich psychopathological picture of schizophrenia, which, beside the core paranoid-hallucinatory syndrome, includes a negative syndrome, a cognitive syndrome and also a depressive syndrome, or whether depression and schizophrenia should be seen as separate conditions in terms of the concept of comorbidity.”113

Bartels and Drake114 suggested that depressive symptoms in schizophrenia be divided into 3 subtypes, including (1) depressive symptoms secondary to organic factors, (2) “nonorganic” depression intrinsic to the acute psychotic episode, and (3) depressive symptoms that are not temporally associated with the acute psychotic episode, such as symptoms associated with the prodrome, the postpsychotic interval, as well as those symptoms that resemble depression that may represent negative symptoms of schizophrenia. Such approaches offer a structure for considering the various relations of depressive symptoms in patients with schizophrenia and are addressed below.

Antipsychotic medications themselves produce neurological side effects like Parkinsonism (particularly bradykinesia, diminution of affective expression, masked facies, and verbal delays) and akathitic restlessness that may be confused with the psychomotor retardation or agitation of depression. Antipsychotic drugs may also produce a primary dysphoria, possibly due to dopamine blockade in reward pathways, and it has even been suggested that these drugs are innately depressogenic. People with schizophrenia are also prone to general medical morbidities115 and substance use disorders,116 some of which may also produce depressive symptoms. Certain negative symptoms, such as anhedonia, abulia, alogia, amotivational and avolitional states, and social withdrawal, can overlap with or spuriously suggest depression.117 Demoralization,118 disappointment, or loneliness119 following a psychotic episode may create lingering feelings of dysphoria.

The classic construct of depression in schizophrenia is that of postpsychotic depression (PPD), defined in an appendix of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,8 as a major depressive episode that is superimposed on, and occurs only during the residual phase of schizophrenia. PDD has traditionally been formulated as a psychological reaction to loss or to the psychological trauma of the psychotic episode. Roth wrote that the “depressive reaction that follows (a psychotic episode) is part and parcel of a total psychobiologic reaction to a failure of the patient in some area of human relationships.”120 The relationship of PPD to the psychotic episode itself remains unclear, including the question of whether the depression is a reaction to psychosis, or represents an unmasking effect of the depression as the psychosis remits.121 This latter view is supported by observations that depressive symptoms are often associated with positive symptom scores122 and decrease with effective neuroleptic treatment. There is a long-standing literature that depression is a common symptom found during psychotic decompensation.123

In contrast to early views that depression was associated with favorable prognosis in schizophrenia, the evidence speaks otherwise. Mandel et al124 followed 211 schizophrenia patients in the community for a year after hospital discharge. The 25% of patients who suffered depression in the first few months after discharge had a notably greater burden of symptom chronicity. Johnson125 reported that chronic patients who developed depression more than a year after acute recovery experienced more relapses than other patients. An older study by Tsuang and Coryell126 and a more recent one by Sim et al127 both failed to reveal better outcomes in schizoaffective disorder than schizophrenia.

Patients with schizophrenia are at increased risk of developing depression relative to the already high lifetime prevalence of depression in the general population. Many investigators have reported rates of depressive psychopathology in psychotic patients,128–166 a summary of which is shown in table 4. As might be expected, the measured rates of depressive experience varied widely. There is methodological diversity in this literature due to varying definitions for schizophrenia (or psychotic illness), heterogenous study populations, and varying time intervals over which depressive occurrence was considered, ranging from point prevalence to many years. Nonetheless, as was noted in the outstanding review by Siris and Bench,4 the above-cited studies have convincingly indicated that patients with schizophrenia were prone to elevated rates of depression, with a modal frequency of about 25%.

Table 4.

Incidence of Prevalence of Secondary Depression in Schizophrenia (Modified From Siris and Bench)4

Study Definition of Psychosis Definition of “Postpsychotic” Interval Definition of Depression Percentage Depressed 
McGlashan and Carpenter128 30 IPSS: more than 90% chance of schizophrenia Cross-sectional at discharge and 1-year follow-up ‘Depression’ per PSE Discharge: 43% 
1-yr: 50% 
Weissman et al129 50 Outpatients with New Haven Schizophrenia Index diagnosis of schizophrenia Point prevalence Raskin Scale score of 7 or more 28% 
Van Putten and May130 94 Newly admitted patients; Feighner criteria for schizophrenia Length of acute hospital stay Increase in BPRS depression rating 38% 
Knights et al131 37 CATEGO criteria: 87% = unequivocal schizophrenia 6 months or until relapse while on depot neuroleptic PSE-based depression rating 54% 
Roy (1980)5 100 DSM-III chronic paranoid schizophrenia Chart review for mean of 6 years DSM-III for major depressive disorder, secondary type 30% 
Johnson133      
Cohort A: 41 Schizophrenia diagnosis based on Schneiderian first-rank symptoms A: 2 months prospective prevalence study A: HAM-D &/or BDI ≥ 15 A: 24% 
Cohort B: 100 Outpatients free of acute symptoms for ≥ 3 months B: Cross-sectional prevalence B: Nurse & self-rating B: 26% 
Cohort C: 30 Patients maintained on depot neuroleptic C: 2-year follow-up C: HAM-D and/or BDI ≥ 15 C: 50% excluding episodes associated w/ psychotic relapse 
Siris et al134 50 Acutely admitted inpatients diagnosed by RDC Duration of hospitalization after resolution of flagrant psychotic symptoms RDC for major or minor depression by chart review 6% major, 22% minor depression 
Roy (1981) 100 DSM-III for schizophrenia Chart review: 4-10 years Treated for depression by antidepressants or ECT 39% 
Moller and von Zerssen136 81 Inpatients with schizophrenia (77%) or paranoid psychosis (23%) by ICD criteria Point prevalence at hospital discharge 3 consecutive Actual Mood Scores ≥ 21 23% 
Guze et al137and Martin et al138 44 Feighner criteria for schizophrenia Retrospective survey at 6-12 year follow-up point Criteria close to Feighner criteria for depression 57% 
Summers et al139  RDC schizophrenia:    
Cohort A: 161 Cohort A: chronic A: admission to aftercare A: SCL-90 scales A: Schiz. more depressed vs. normals 
Cohort B: 72 Cohort B: Acute B: past month assessment (average 2.13 year post discharge) B: 2 composite depression scales from KAS B: 37% poor; 68% poor or equivocal 
Watt and Shepherd (1983) (reported in Roy140 121 Chronic schizophrenia (PSE criteria) PSE: Admission, 1 month, 1 year, & 5 years after discharge PSE assessment of depression syndrome 40% at 1 mo., 1 yr. (‘severe’ in ¼ of these); 19% at 5 yrs 
Munro et al141 100 Outpatients with DSM-III for schizophrenia Clinic cross-sectional prevalence Carroll Rating Scale 41% (10% severe, 18% moderate, 13% mild) 
Elk et al142 56 CATEGO ‘S’ diagnosis Point prevalence at hospital admission PSE depressed mood + observed depression 30% 
Leff et al143 31 Newly admitted patients with PSE/CATEGO schizophrenia Until discharged or until 6 months Depressed mood by PSE 45% 
Johnson (1988)17 80 Feighner schizophrenia criteria; Period began when patients were free of acute symptoms Altered mood x ≥ 7 days with HAM-D & BDI each > 15: DSM-III for depression Period A: 13-30% 
Period A: 0-12 months 
Schneiderian first-rank symptoms Period B: 12-36 months Period B: 65% 
(ratings ≥ every 3 months) 
Kulhara et al145 95 Outpatients with ICD-9 diagnosis of schizophrenia Cross-sectional assessment Depressed mood on PSE 32% 
Hirsch et al (1989)19  DSM-III schizophrenia    
Cohort A: 46 Cohort A: Thought by nurses to be ‘depressed’ A & B: Cross-sectional assessment A: HAM-D & BDI A: 7% 
Cohort B: (also Barnes et al 1989)20 196 Cohort B: Long-stay inpatients  B: Depression item on PSE B: 13% 
Cohort C: 44 Cohort C: Outpatients with no florid symptoms in previous 6 months Cohort C: Bimonthly assessments × 1 year while randomly assigned to depot neuroleptic or placebo C: Manchester Scale depression item ≥ 2 C: 73% of psychotic relapses: prodrome included depression 
Bandelow et al148 364 ICD-9 and RDC for schizophrenia Point prevalence 3 months after discharge and acute stabilization on neuroleptic medication BPRS anxious-depression scale ≥ 10 19.5% 
Addington and Addington149 50 DSM-III Schizophrenia Point prevalence DSM-III depressive episode by PSE 24% 
Breier et al150 58 RDC schizophrenia (N = 42) or schizoaffective disorder Average follow-up = 6 + 3 years RDC major depression 24% 
(N = 16; 12 depressed type) 
Lindenmayer et al151 240 Mostly chronic inpatients with DSM-III schizophrenia Point-prevalence ‘Severe’ PANSS depression component > 19; ‘mild to moderate’ 11-18 5% severe depression 
52% mild to moderate 
Birchwood et al152 49 CATEGO class ‘s’ for schizophrenia Randomly selected from urban outpatient ‘depot’ treatment clinic Score of at least 15 on the BDI 29% 
Koreen et al153 70 ‘First break’, RDC for schizophrenia (77%) or schizoaffective disorder (23%) Repeated prospective assessment at weekly intervals during acute treatment, and monthly intervals thereafter up to 5 years Syndromal depression &/or extracted HAM-D based on SADS interview 75% (met one criterion at some point); 22% (met both criteria concurrently) 
Tapp et al154 91 DSM-IIIR & RDC for schizophrenia per SADS Not stated HAM-D rating (not specified) 37% (non-Kraepe- linian); 6% (Krae- linian) 
Harrow et al155 54 RDC schizophrenia Prevalence during 1 year before interview which was 4.5 years (avg) after hospital discharge of index psychotic episode Full depressive RDC syndrome 37% 
Mauri et al156 43 Chronic schizophrenic inpatients (DSM-IIIR) acute exacerbation Prevalence at baseline and after 6 weeks of neuroleptic treatment HAM-D & BPRS depression subscale 16.3%: moderate symptoms of depression 
(23.2%: mild sx) 
Markou157 94 DSM-IIIR Schizophrenia; 50 inpatients & 44 chronic hospital outpatients Point prevalence ‘Significant depression’ (HAM-D > 17) ‘mild to moderate depression’ (10- 17) Inpatients: 
10% significant 
42% mild-moderate 
Outpatients: 
4.5% significant 
48% mild-moderate 
Wassink et al158 62 Recent onset DSM-IIIR or DSM-IV schizophrenia Point prevalence DSM-IV major depressive disorder 35% 
Muller and Wetzel159 132 Acute DSM-IIIR schizophrenia Point prevalence BRMES ≥ 14 42% 
Sands and Harrow160 70 RDC schizophrenia Assessed 7.5 years after discharge; covers the previous year RDC depression, full syndrome vs. subsyndromal 36%: full syndrome 
14%: subsyndromal 
Zisook et al161 60 Outpatients with DSM-IIIR or DSM-IV schizophrenia, age 45-79 Point prevalence HAM-D ≥ 17 Women: 20% 
Men: 7% 
Baynes et al (2000)35 120 Stable outpatients, DSM-IIIR chronic schizophrenia Point prevalence BDI ≥ 17 13.3% (+ 24.2% with BDI = 10-16) 
Bottlender et al163 998 First hospitalization, ICD-9 schizophrenia Point prevalence AMDP depression syndrome score ≥ 8 AMDP Dep≥ 8: 21% 
“Clinically significant depression”: 15.5% 
Bressan et al164 80 Stable outpatients, DSM-V schizophrenia Time since last psychosis; range = 2 mos-15 years DSV-IV major depressive episode 16.3% 
Serretti et al165 358 Inpatients/outpatients with various diagnoses (n=1351); 358 w/OPCRIT schizophrenia Point prevalence ≥4 OPCRIT depressive symptoms 26.8% 
Hafner et al (2005)39 232 First-admission schizophrenics, age 12-59 Retrospective assessment of lifetime prevalence Depressed mood for ≥ 2 weeks before first admission per IRAOS interview 83% 
Study Definition of Psychosis Definition of “Postpsychotic” Interval Definition of Depression Percentage Depressed 
McGlashan and Carpenter128 30 IPSS: more than 90% chance of schizophrenia Cross-sectional at discharge and 1-year follow-up ‘Depression’ per PSE Discharge: 43% 
1-yr: 50% 
Weissman et al129 50 Outpatients with New Haven Schizophrenia Index diagnosis of schizophrenia Point prevalence Raskin Scale score of 7 or more 28% 
Van Putten and May130 94 Newly admitted patients; Feighner criteria for schizophrenia Length of acute hospital stay Increase in BPRS depression rating 38% 
Knights et al131 37 CATEGO criteria: 87% = unequivocal schizophrenia 6 months or until relapse while on depot neuroleptic PSE-based depression rating 54% 
Roy (1980)5 100 DSM-III chronic paranoid schizophrenia Chart review for mean of 6 years DSM-III for major depressive disorder, secondary type 30% 
Johnson133      
Cohort A: 41 Schizophrenia diagnosis based on Schneiderian first-rank symptoms A: 2 months prospective prevalence study A: HAM-D &/or BDI ≥ 15 A: 24% 
Cohort B: 100 Outpatients free of acute symptoms for ≥ 3 months B: Cross-sectional prevalence B: Nurse & self-rating B: 26% 
Cohort C: 30 Patients maintained on depot neuroleptic C: 2-year follow-up C: HAM-D and/or BDI ≥ 15 C: 50% excluding episodes associated w/ psychotic relapse 
Siris et al134 50 Acutely admitted inpatients diagnosed by RDC Duration of hospitalization after resolution of flagrant psychotic symptoms RDC for major or minor depression by chart review 6% major, 22% minor depression 
Roy (1981) 100 DSM-III for schizophrenia Chart review: 4-10 years Treated for depression by antidepressants or ECT 39% 
Moller and von Zerssen136 81 Inpatients with schizophrenia (77%) or paranoid psychosis (23%) by ICD criteria Point prevalence at hospital discharge 3 consecutive Actual Mood Scores ≥ 21 23% 
Guze et al137and Martin et al138 44 Feighner criteria for schizophrenia Retrospective survey at 6-12 year follow-up point Criteria close to Feighner criteria for depression 57% 
Summers et al139  RDC schizophrenia:    
Cohort A: 161 Cohort A: chronic A: admission to aftercare A: SCL-90 scales A: Schiz. more depressed vs. normals 
Cohort B: 72 Cohort B: Acute B: past month assessment (average 2.13 year post discharge) B: 2 composite depression scales from KAS B: 37% poor; 68% poor or equivocal 
Watt and Shepherd (1983) (reported in Roy140 121 Chronic schizophrenia (PSE criteria) PSE: Admission, 1 month, 1 year, & 5 years after discharge PSE assessment of depression syndrome 40% at 1 mo., 1 yr. (‘severe’ in ¼ of these); 19% at 5 yrs 
Munro et al141 100 Outpatients with DSM-III for schizophrenia Clinic cross-sectional prevalence Carroll Rating Scale 41% (10% severe, 18% moderate, 13% mild) 
Elk et al142 56 CATEGO ‘S’ diagnosis Point prevalence at hospital admission PSE depressed mood + observed depression 30% 
Leff et al143 31 Newly admitted patients with PSE/CATEGO schizophrenia Until discharged or until 6 months Depressed mood by PSE 45% 
Johnson (1988)17 80 Feighner schizophrenia criteria; Period began when patients were free of acute symptoms Altered mood x ≥ 7 days with HAM-D & BDI each > 15: DSM-III for depression Period A: 13-30% 
Period A: 0-12 months 
Schneiderian first-rank symptoms Period B: 12-36 months Period B: 65% 
(ratings ≥ every 3 months) 
Kulhara et al145 95 Outpatients with ICD-9 diagnosis of schizophrenia Cross-sectional assessment Depressed mood on PSE 32% 
Hirsch et al (1989)19  DSM-III schizophrenia    
Cohort A: 46 Cohort A: Thought by nurses to be ‘depressed’ A & B: Cross-sectional assessment A: HAM-D & BDI A: 7% 
Cohort B: (also Barnes et al 1989)20 196 Cohort B: Long-stay inpatients  B: Depression item on PSE B: 13% 
Cohort C: 44 Cohort C: Outpatients with no florid symptoms in previous 6 months Cohort C: Bimonthly assessments × 1 year while randomly assigned to depot neuroleptic or placebo C: Manchester Scale depression item ≥ 2 C: 73% of psychotic relapses: prodrome included depression 
Bandelow et al148 364 ICD-9 and RDC for schizophrenia Point prevalence 3 months after discharge and acute stabilization on neuroleptic medication BPRS anxious-depression scale ≥ 10 19.5% 
Addington and Addington149 50 DSM-III Schizophrenia Point prevalence DSM-III depressive episode by PSE 24% 
Breier et al150 58 RDC schizophrenia (N = 42) or schizoaffective disorder Average follow-up = 6 + 3 years RDC major depression 24% 
(N = 16; 12 depressed type) 
Lindenmayer et al151 240 Mostly chronic inpatients with DSM-III schizophrenia Point-prevalence ‘Severe’ PANSS depression component > 19; ‘mild to moderate’ 11-18 5% severe depression 
52% mild to moderate 
Birchwood et al152 49 CATEGO class ‘s’ for schizophrenia Randomly selected from urban outpatient ‘depot’ treatment clinic Score of at least 15 on the BDI 29% 
Koreen et al153 70 ‘First break’, RDC for schizophrenia (77%) or schizoaffective disorder (23%) Repeated prospective assessment at weekly intervals during acute treatment, and monthly intervals thereafter up to 5 years Syndromal depression &/or extracted HAM-D based on SADS interview 75% (met one criterion at some point); 22% (met both criteria concurrently) 
Tapp et al154 91 DSM-IIIR & RDC for schizophrenia per SADS Not stated HAM-D rating (not specified) 37% (non-Kraepe- linian); 6% (Krae- linian) 
Harrow et al155 54 RDC schizophrenia Prevalence during 1 year before interview which was 4.5 years (avg) after hospital discharge of index psychotic episode Full depressive RDC syndrome 37% 
Mauri et al156 43 Chronic schizophrenic inpatients (DSM-IIIR) acute exacerbation Prevalence at baseline and after 6 weeks of neuroleptic treatment HAM-D & BPRS depression subscale 16.3%: moderate symptoms of depression 
(23.2%: mild sx) 
Markou157 94 DSM-IIIR Schizophrenia; 50 inpatients & 44 chronic hospital outpatients Point prevalence ‘Significant depression’ (HAM-D > 17) ‘mild to moderate depression’ (10- 17) Inpatients: 
10% significant 
42% mild-moderate 
Outpatients: 
4.5% significant 
48% mild-moderate 
Wassink et al158 62 Recent onset DSM-IIIR or DSM-IV schizophrenia Point prevalence DSM-IV major depressive disorder 35% 
Muller and Wetzel159 132 Acute DSM-IIIR schizophrenia Point prevalence BRMES ≥ 14 42% 
Sands and Harrow160 70 RDC schizophrenia Assessed 7.5 years after discharge; covers the previous year RDC depression, full syndrome vs. subsyndromal 36%: full syndrome 
14%: subsyndromal 
Zisook et al161 60 Outpatients with DSM-IIIR or DSM-IV schizophrenia, age 45-79 Point prevalence HAM-D ≥ 17 Women: 20% 
Men: 7% 
Baynes et al (2000)35 120 Stable outpatients, DSM-IIIR chronic schizophrenia Point prevalence BDI ≥ 17 13.3% (+ 24.2% with BDI = 10-16) 
Bottlender et al163 998 First hospitalization, ICD-9 schizophrenia Point prevalence AMDP depression syndrome score ≥ 8 AMDP Dep≥ 8: 21% 
“Clinically significant depression”: 15.5% 
Bressan et al164 80 Stable outpatients, DSM-V schizophrenia Time since last psychosis; range = 2 mos-15 years DSV-IV major depressive episode 16.3% 
Serretti et al165 358 Inpatients/outpatients with various diagnoses (n=1351); 358 w/OPCRIT schizophrenia Point prevalence ≥4 OPCRIT depressive symptoms 26.8% 
Hafner et al (2005)39 232 First-admission schizophrenics, age 12-59 Retrospective assessment of lifetime prevalence Depressed mood for ≥ 2 weeks before first admission per IRAOS interview 83% 

BDI = Beck Depression Inventory; BPRS = Brief Psychiatric Rating Scale; BRMES = Bech-Rafaelsen Melancholia Scale; DSM = Diagnositc & Statistical Manual; HAM-D = Hamilton Depression Rating Scale; ICD = International Classification of Diseases; IPSS = International Pilot Study or Schizophrenia; IRAOS = Interview for the Retrospective Assessment of the Onset of Schizophrenia; KAS = Katz Adjustment Scale; OPCRIT = Operational Criteria for Psychotic Illness; PANSS = Positive & Negative Syndrome Scale; PSE = Present State Examination; RDC = Research Diagnostic Criteria; SADS = Schedule for Affective Disorders & Schizophrenia; SCL-90 = Symptom Checklist, 90 item.

It is instructive to examine the likelihood that major depressive episodes will evolve into psychosis, and indeed, depressed patients are at high risk for developing psychotic symptoms during the course of affective illness. As a whole, however, this has been less thoroughly studied than the likelihood of depression in schizophrenic patients. Ohayon and Schatzberg167studied the point prevalence of depression in a general population sample of 18,980 people surveyed in a multinational European study. About 16.5% of all subjects endorsed at least one key depressive criterion, and of those, 12.5% reported delusions and/or hallucinations. Of the 454 subjects diagnosed with a full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive episode, 18.6% experienced delusions and/or hallucinations. This is consistent with findings that 14% of the ECA community sample diagnosed with major depression168 and 16.9% of an independent first-admission major depression sample169 experienced psychosis during the course of the depressive episode.

Studies of individuals at high risk and ultrahigh risk for developing schizophrenia have generally demonstrated a significant degree of depressive symptoms prior to and during the emergence of psychotic symptoms.170–172 Cornblatt et al173 identified affective disturbances and social isolation as part of an “underlying vulnerability core” in a group of 62 adolescents in various stages of emerging psychosis. Hafner et al169 obtained comprehensive histories from 232 mostly previously untreated, first-admission adult, and teenaged patients diagnosed with schizophrenia, as well as 130 healthy controls and 130 demographically matched, first-admission patients with a diagnosis of depression. In comparing a subset of 130 patients with schizophrenia with the primary depression group, the authors generated lists of the 10 most frequent initial symptoms of illness for depressed and schizophrenia groups, resulting in a combined and highly overlapping list consisting of 13 symptoms. Eight of the 13 most common symptoms did not differ significantly in the frequency. Both diagnostic groups had suffered from both a depressive core syndrome and negative syndrome (difficulties in thinking and concentration, loss of energy, social withdrawal) in the early course of illness, with closely paralleling courses. Patients with schizophrenia were most distinguished, not surprisingly, by markedly escalating positive symptoms leading up to the index admission. The authors concluded that that the initial symptoms of illness reflected a core psychopathology common to the very early stages of both illnesses. They also noted that the peak of depressive experience in patients with schizophrenia coincided with peak psychosis.

Concerning the neurobiology of schizophrenia and depression and evidence of etiologic and pathophysiologic coincidence or overlap, the majority of studies that might inform the topic utilize subjects with either depression or schizophrenia but rarely both. While functional imaging studies of depressed patients have shown decreased prefrontal metabolism or decreased regional cerebral blood flow (rCBF),174,175 those that directly compared rCBF changes during working memory tasks in schizophrenia and depressed groups showed substantial intergroup differences in the direction of greater reduction of rCBF in schizophrenia than depressed subjects.176,177 Reduced hippocampal volume has been reported in depression and schizophrenia,178–180 and a recent study examined the association between myelin related genes and the clinical characteristics of 280 schizophrenia subjects—specifically the presence or absence of depressive comorbidity.181 The investigators demonstrated an association between the glycoprotein M6A gene (GPM6A)—a modulator of the influence of stress on the hippocampus in animals—with the subgroup of schizophrenia patients who showed the highest degree of depression.

In contrast, one of the most consistent functional imaging findings in depression concerns increased rCBF or glucose metabolism in the amygdala of ill subjects relative to healthy controls.182 This finding is absent in patients with schizophrenia who, if anything, show diminished amygdalar activity relative to controls.183 What is missing in the literature is direct comparison of neurobiological variables between patients with schizophrenia with and without comorbid depression.

Much has been written about the newer generation antipsychotic drugs and the potential advantage in psychotic patients with depression, including avoidance of dopamine blockade dysphoria and extrapyramidal side effects (EPS). The newer drugs’ unique pharmacologic features, particular affinity at various serotonergic receptors, may well confer some direct and indirect advantages.184

Tollefson et al185 raised the possibility that SGAs—in this instance olanzapine—may have a direct effect on a depressive symptom domain in patients with schizophrenia. In a path analysis of depression in schizophrenia and its treatment with either olanzapine or haloperidol, they reported superiority for olanzapine and that 56% of this effect on depressive symptoms was on “primary” symptoms rather than secondary to negative symptoms, relief of EPS, etc. Similar analyses have been conducted for other SGAs.186,187 Moreover, clozapine's antisuicide effect did not appear to be related to (merely) better amelioration of symptoms because both clozapine and olanzapine fared equally well on positive, negative, and depressive symptom improvements.188 Moreover, the now widespread use of SGAs in bipolar disorder is additional indirect evidence for some independence of effects on mood and not simply an “antipsychotic” effect (to reduce positive symptoms, thereby lessening depression) in schizophrenia.

From a different vantage point, the role of antidepressant therapy in schizophrenia has received relatively little attention, particularly given the frequency of depressive symptoms and the regular copharmacy (in approximately 30% of patients) of antidepressants and antipsychotics when treating patients with schizophrenia. Interestingly, Siris et al189 showed that adjunctive imipramine improved depression and also resulted in fewer psychotic relapses. The information concerning adjunctive antidepressant therapy with SGAs is particularly scant. Whether, in view of their effect on neuroplasticity, these drugs might have broader clinical effects beyond treating comorbid depressive symptoms in schizophrenia is of interest. Cornblatt et al190 found that prepsychotic adolescents who received antidepressants did just as well as prepsychotic patients who were treated with antipsychotics. Although a naturalistic study, the potential that antidepressants may impact the development of psychosis is intriguing and provocative.

In concluding this section, the following observations can be made: (1) depressive symptoms are common in patients with schizophrenia; (2) they add further to the disability of schizophrenia, including being associated with a heightened risk for psychotic relapses; (3) PPD may be a particular “forme fruste” of major depression in schizophrenia; (4) there is some evidence, far from conclusive, that medications might directly impact depressive, mood, and suicidality to some extent that is not simply “less depression because of less psychosis”; and (5) although intuitively appealing, there is insufficient evidence in the literature (including a dearth of neurobiological studies) to support the proposition that this represents a distinct subgroup of schizophrenia.

Substance Abuse Comorbidity

The abuse of alcohol and/or illicit drugs by patients with schizophrenia is a remarkably common phenomenon …“the rule rather than the exception.10,191 In the ECA study, it was estimated that 47% of patients with schizophrenia also had a lifetime diagnosis of substance abuse disorder.191 This is consistent with findings from a variety of other epidemiological and clinical studies, both in the United States and worldwide.10,191–194 In general terms, substance abuse comorbidity is associated with a variety of negative consequences for the course of schizophrenia (see table 5), with medication nonadherence often appearing as a “final common pathway” for these effects. Description of the epidemiology and consequences of substance abuse and schizophrenia is beyond the scope of this article and is accounted well elsewhere.8 Suffice it to say that substance abuse comorbidity is common and is deleterious to the course and outcome of schizophrenia. The investigation of this co-occurrence has been (perhaps to a greater extent than the other comorbidities) hampered by a general effort to exclude patients with comorbid substance abuse when studying schizophrenia. Thus, sampling bias is an important consideration in evaluating this association.

Table 5.

Consequences of Comorbid Substance Abuse in Patients With Schizophrenia

More positive symptoms 
Relapse of psychosis 
Heightened risk of violence 
Heightened risk of suicide 
More medical comorbidities 
Legal complications, including heightened risk of incarceration 
Greater propensity to antipsychotic-related side effects 
More positive symptoms 
Relapse of psychosis 
Heightened risk of violence 
Heightened risk of suicide 
More medical comorbidities 
Legal complications, including heightened risk of incarceration 
Greater propensity to antipsychotic-related side effects 

Explanations for the common association of substance abuse with schizophrenia are highlighted. Firstly, one might consider this merely a chance co-occurrence, particularly because adolescents and young adults abuse drugs. Why should adolescents/young adults with schizophrenia be any less likely to do this? Epidemiological data and clinical experience suggest that this is not merely a “chance occurrence” and that it is frequent and beyond mere coincidence.191–193 Furthermore, it seems that both patterns of use and motivations for use are very similar in individuals with schizophrenia, as in the nonschizophrenia population.

The second notion is that alcohol or drugs actually caused schizophrenia and that this explains the co-occurrence. Heavy and protracted abuse of alcohol has been causally associated with a discrete alcoholic hallucinosis, but this is relatively rare and the longitudinal course is usually not the same as schizophrenia, such that, eg, affect and personality are relatively preserved. Any strong causal association between alcohol and schizophrenia per se is difficult to envisage given the ubiquity of alcohol use and the fact that the vast majority of people who do use alcohol to excess do not develop schizophrenia. The evidence for illicit drugs being causally associated with schizophrenia is at best mixed but has been most compelling argued for cannabis. A number of cohort studies have now established a temporal relationship between cannabis exposure in adolescence or early adulthood, and later schizophrenia, with an odds ratio of just over 2.0 (2.09, with confidence intervals of 1.54–2.84) in a recent metaanalysis of these studies.195 Additionally, some studies show a “dose-dependent” effect, such the more cannabis consumed the greater the likelihood of schizophrenia.196 However, again the prevalence of schizophrenia is disproportionate to the ubiquitous smoking of cannabis, there is no clear association between rates of schizophrenia and rates of cannabis use in any given population, and most people who imbibe cannabis do not develop schizophrenia. Thus, it seems that cannabis can be conceptualized as a cumulative causal factor in some individuals, acting in concert with other vulnerability factors to promote the manifestation of the illness in some individuals who might otherwise have remained schizophrenia free. The effect is small, with a population attributable fraction of 5%–7%. Also, it does not appear that patients with schizophrenia and comorbid cannabis have any higher genetic loading for schizophrenia than patients with schizophrenia alone.197

Caton et al198 examined the relationship between substance-induced psychosis and schizophrenia by longitudinally evaluating patients who presented acutely psychotic, all of whom had abused drugs or alcohol prior to this first ever presentation with psychosis. Forty-four percent of patients turned out over time to have had a drug-induced psychosis, while 56% of patients ultimately had schizophrenia as their primary diagnosis. Patients with a drug-related psychosis had marginally less positive and negative symptoms at initial presentation, they were more likely to have visual hallucinations, and their parents had a history of substance abuse. Caspi et al11 examined this issue from a different, complementary perspective. As part of a large epidemiological study of schizophrenia in New Zealand, they found that those adolescents who possessed the “faulty” allele (val 158 met) polymorphism of the COMT (cathechol -O-methyl-transferase) gene were the people who had the vulnerability to cannabis abuse. This might help explain this association, which appears robust from epidemiological data but is still a small effect. There is a recent study of brain imaging in nonpsychotic cannabis abusers that shows progressive brain changes with heavy and chronic cannabis abuse.199 The authors report some association between paranoid experiences in a subset of these patients and greater prominence of hippocampal changes. As a general observation, there have been few biological studies of this dual diagnosis patient population because substance abuse is more often than not an exclusionary criterion. On the other hand, there is a growing appreciation of potentially shared neurochemical vulnerability between substance abuse and schizophrenia.200 Animal neurochemical and now human brain imaging studies point to the role of dopamine in the amygdala as being key to understanding drug craving and reward behaviors. In schizophrenia, pleasure and reward are blunted as part of negative symptoms. It is plausible that dopamine dysregulation might predispose patients with schizophrenia to abuse drugs.194,200 It has also been explained that patients with schizophrenia who abuse drugs may actually have milder symptoms and that their poorer course is more attributable to the direct effect of drugs on worsening symptoms as well as the associated medication nonadherence. This is certainly intuitive in the sense that patients with more severe illness are less likely to have the opportunity and social context to acquire street drugs. It has also long been suggested that patients self medicate either to reduce their symptoms or to counteract the effects of antipsychotic medications.201,202 Either association is plausible and in accord with clinical experience. However, the rate of substance abuse comorbidity has not seemed to diminish in an era of treatment with SGAs that have less motor and secondary negative symptom effects.203 Regarding treatment of patients with substance abuse, these patients show similar responses to antipsychotic medications as nonabusing patients with schizophrenia—once they take their medication, a major challenge in this patient group.20,204 In the clinical antipsychotic trials of intervention effectiveness (CATIE) study, patients with comorbid substance abuse showed comparable responses with each SGA than patients without substance abuse.205 There is some evidence that dual diagnosis patients might do better on clozapine, with less relapse into abuse of drugs or alcohol.206

Overall, while substance abuse comorbidity is remarkably common in schizophrenia, the evidence is lacking that this represents some distinct subgroup of etiopathological significance. While explanations toward a shared neurochemical, dopamine-mediated vulnerability to both schizophrenia and substance abuse are intuitively appealing, at present the evidence base is scant.194 Moreover, the prevailing view in both the addiction field and in schizophrenia research is that this represents a co-occurrence of 2 conditions rather than some etiologically distinct subgroup of schizophrenia patients who are characterized by a proclivity to substance abuse.

Conclusions

There is clearly an increased prevalence of anxiety, depressive, and substance abuse disorders in patients with schizophrenia that occurs in excess of that in the general population. These comorbidities occur at all phases of the course of illness, including in the psychosis prodrome, FEP, and chronic schizophrenia. A limited body of evidence supports the plausibility of the hypothesis that anxiety disorders are part of the illness of schizophrenia, with the strongest evidence being for OCD. PTSD, and other anxiety symptoms, while common, do not appear to be etiologically linked to schizophrenia. Depressive symptoms are also intrinsic to the illness and import a poorer outcome, including more psychotic relapses. Understanding this relationship is important and is also additionally complicated by broader perspectives about the boundaries/overlap between psychosis and mood disorders. Substance abuse is particularly common and also worsens the course of illness, although here this effect is inextricably linked to treatment noncompliance. For each of these comorbidities, their presence is generally associated with more severe psychopathology and with poorer outcomes. What is conspicuous from this review is the relative lack of investigation toward a neurobiological basis of comorbidity among patients with schizophrenia. This is striking in view of how common and challenging these comorbidities are. There is a conspicuous absence of any “smoking gun” findings for etiological heterogeneity here. While there has been at least some headway in treatment studies of both pharmacology and nonpharmacology, it is rudimentary and in relation to OCD and schizophrenia there is the suggestion that antipsychotic medications might even aggravate these symptoms.3 There is also, on the other hand, evidence that antidepressants can not just improve depressive symptoms but perhaps also impact favorably negative and general psychopathology as well.5 These observations may contribute in part to the high rates of polypharmacy that are observed in the treatment of schizophrenia.207 At present, the therapeutic implications of this clinical heterogeneity are poorly understood and are largely manifested in “trial and error” treatment choices. The most parsimonious conclusion at the present time is that these comorbidities are certainly more common than chance in schizophrenia, but their etiopathological significance and treatment implications thereupon are poorly understood at the present time.

References

1.
Kirkpatrick
B
Buchanan
RW
Ross
DE
Carpenter
WT
Jr
A separate disease within the syndrome of schizophrenia
Arch Gen Psychiatry
 , 
2001
, vol. 
58
 (pg. 
165
-
171
)
2.
Pincus
HA
Tew
D
First
MB
Psychiatric comorbidity: is more less?
World Psychiatry
 , 
2004
, vol. 
3
 (pg. 
18
-
23
)
3.
Green
AI
Canuso
C
Brenner
MJ
Wijcik
JD
Detection and management of comorbidity in schizophrenia
Psychiatr Clin N Am
 , 
2003
, vol. 
26
 (pg. 
115
-
139
)
4.
Siris
S
Bench
C
Hirsch
S
Weinberger
D
Depression and schizophrenia
Schizophrenia
 , 
2003
2nd ed.
Oxford, UK
Blackwell
(pg. 
142
-
167
)
5.
Moller
HJ
Drug treatment of depressive symptoms in schizophrenia
Clin Schizophr Relat Psychoses
 , 
2007
, vol. 
1
 (pg. 
328
-
340
)
6.
Kendell
RE
The classification of depressions: a review of contemporary confusion
Br J Psychiatry
 , 
1976
, vol. 
129
 (pg. 
15
-
28
)
7.
Pierre
JM
Deconstructing schizophrenia for DSM-V: challenges for clinical and research agendas
Clin Schizophr Relat Psychoses
 , 
2008
, vol. 
2
 (pg. 
166
-
174
)
8.
Wing
J
Agrawal
N
Hirsch
S
Weinberger
D
Concepts and classification of schizophrenia
Schizophrenia
 , 
2003
2nd ed.
Oxford, UJK
Blackwell
(pg. 
3
-
14
)
9.
American Psychiatric Association
Diagnostic and Statistical Manual of Mental Disorders
 , 
2000
Fourth edition, Text Revision
Washington, DC
American Psychiatric Association
10.
Buckley
PF
Prevalence and consequences of the dual diagnosis of substance abuse and severe mental illness
J Clin Psychiatry
 , 
2006
, vol. 
67
 (pg. 
5
-
9
)
11.
Caspi
A
Moffitt
TE
Cannon
M
, et al.  . 
Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-0-methyltransferase gene: longitudinal evidence of a gene x environment interaction
Biol Psychiatry
 , 
2005
, vol. 
57
 (pg. 
1117
-
1127
)
12.
Bermanzohn
PC
Porto
L
Arlow
PB
Pollack
S
Stronger
R
Siris
SG
Hierarchical diagnosis in chronic schizophrenia: a clinical study of co-occurring syndromes
Schizophr Bull.
 , 
2000
, vol. 
26
 (pg. 
517
-
525
)
13.
Pokos
V
Castle
DJ
Prevalence of comorbid anxiety disorders in schizophrenia spectrum disorders: a literature review
Curr Psychiatry Rev
 , 
2006
, vol. 
2
 (pg. 
285
-
307
)
14.
Boyd
JH
Use of mental health services for the treatment of panic disorder
Am J Psychiatry
 , 
1986
, vol. 
143
 (pg. 
1569
-
1574
)
15.
Goodwin
R
Lyons
JS
McNally
RJ
Panic attacks in schizophrenia
Schizophr Res
 , 
2002
, vol. 
58
 (pg. 
213
-
220
)
16.
Boyd
JH
Burke
JD
Jr
Gruenberg
E
, et al.  . 
Exclusion criteria of DSM-III. A study of co-occurrence of hierarchy-free syndromes
Arch Gen Psychiatry
 , 
1984
, vol. 
41
 (pg. 
983
-
989
)
17.
Robins
LN
Regier
DA
Psychiatric Disorders in America: the Epidemiological Catchment Area Study
1991
New York, NY
The Free Press
18.
Argyle
N
Panic attacks in chronic schizophrenia
Br J Psychiatry
 , 
1990
, vol. 
157
 (pg. 
430
-
433
)
19.
Baylé
FJ
Krebs
MO
Epelbaum
C
Levy
D
Hardy
P
Clinical features of panic attacks in schizophrenia
Eur Psychiatry
 , 
2001
, vol. 
16
 (pg. 
349
-
353
)
20.
Bland
RC
Newman
SC
Orn
H
Schizophrenia: lifetime co-morbidity in a community sample
Acta Psychiatr Scand
 , 
1987
, vol. 
75
 (pg. 
383
-
391
)
21.
Cassano
GB
Pini
S
Saettoni
M
Rucci
P
Dell-Osso
L
Occurrence and clinical correlates of psychiatric comorbidity in patients with psychotic disorders
J Clin Psychiatry
 , 
1998
, vol. 
59
 (pg. 
60
-
68
)
22.
Chen
CY
Liu
CY
Yang
YY
Correlation of panic attacks and hostility in chronic schizophrenia
Psychiatry Clin Neurosci
 , 
2001
, vol. 
55
 (pg. 
383
-
387
)
23.
Ciapparelli
A
Paggini
R
Marazziti
D
, et al.  . 
Comorbidity with axis I anxiety disorders in remitted psychotic patients 1 year after hospitalization
CNS Spectr
 , 
2007
, vol. 
12
 (pg. 
913
-
919
)
24.
Craig
T
Hwang
MY
Bromet
EJ
Obsessive-compulsive and panic symptoms in patients with first-admission psychosis
Am J Psychiatry
 , 
2002
, vol. 
159
 (pg. 
592
-
598
)
25.
Cosoff
SJ
Hafner
RJ
The prevalence of comorbid anxiety in schizophrenia, schizoaffective disorder and bipolar disorder
Aust N Z J Psychiatry
 , 
1998
, vol. 
32
 (pg. 
67
-
72
)
26.
Cutler
JL
Siris
SG
“Panic-like” symptomatology in schizophrenic and schizoaffective patients with postpsychotic depression: observations and implications
Compr Psychiatry
 , 
1991
, vol. 
32
 (pg. 
465
-
473
)
27.
Garvey
M
Noyes
R
Jr
Anderson
D
Cook
B
Examination of comorbid anxiety in psychiatric inpatients
Compr Psychiatry
 , 
1991
, vol. 
32
 (pg. 
277
-
282
)
28.
Goodwin
RD
Amador
XF
Malaspina
D
Yale
SA
Goetz
RR
Gorman
JM
Anxiety and substance use comorbidity among inpatients with schizophrenia
Schizophr Res
 , 
2003
, vol. 
61
 (pg. 
89
-
95
)
29.
Heun
R
Maier
W
Relation of schizophrenia and panic disorder: evidence from a controlled family study
Am J Med Genet
 , 
1995
, vol. 
60
 (pg. 
127
-
132
)
30.
Higuchi
H
Kamata
M
Yoshimoto
M
Shimisu
T
Hishikawa
Y
Panic attacks in patients with chronic schizophrenia: a complication of long-term neuroleptic treatment
Psychiatry Clin Neurosci
 , 
1999
, vol. 
53
 (pg. 
91
-
94
)
31.
Labbate
LA
Young
PC
Arana
GW
Panic disorder in schizophrenia
Can J Psychiatry
 , 
1999
, vol. 
44
 (pg. 
488
-
490
)
32.
Lyons
MJ
Huppert
J
Toomey
R
, et al.  . 
Lifetime prevalence of mood and anxiety disorders in twin pairs discordant for schizophrenia
Twin Res
 , 
2000
, vol. 
3
 (pg. 
28
-
32
)
33.
Moorey
H
Soni
SD
Anxiety symptoms in stable chronic schizophrenics
J Ment Health
 , 
1994
, vol. 
3
 (pg. 
257
-
262
)
34.
Pallanti
S
Quercioli
L
Hollander
E
Social anxiety in outpatients with schizophrenia: a relevant cause of disability
Am J Psychiatry
 , 
2004
, vol. 
161
 (pg. 
53
-
58
)
35.
Strakowski
SM
Tohen
M
Stoll
AL
, et al.  . 
Comorbidity in psychosis at first hospitalization
Am J Psychiatry
 , 
1993
, vol. 
150
 (pg. 
752
-
757
)
36.
Tibbo
P
Swainson
J
Chue
P
LeMelledo
JM
Prevalence and relationship to delusions and hallucinations of anxiety disorders in schizophrenia
Depress Anxiety
 , 
2003
, vol. 
17
 (pg. 
65
-
72
)
37.
Ulas
H
Alptekin
K
Akdede
BB
, et al.  . 
Panic symptoms in schizophrenia: comorbidity and clinical correlates
Psychiatry Clin Neurosci
 , 
2007
, vol. 
61
 (pg. 
678
-
680
)
38.
Zarate
R
The comorbidity between schizophrenia and anxiety disorders. Paper presented at: 31st Annual Meeting of the Association for Advancement of Behavior Therapy
1997
Miami Beach
Fla
39.
Braga
RJ
Mendlowicz
MV
Marrocos
RP
Figueira
IL
Anxiety disorders in outpatients with schizophrenia: prevalence and impact on the subjective quality of life
J Psychiatr Res
 , 
2005
, vol. 
39
 (pg. 
409
-
414
)
40.
Katerndahl
DA
Realini
JP
Lifetime prevalence of panic states
Am J Psychiatry
 , 
1993
, vol. 
150
 (pg. 
246
-
249
)
41.
Grant
BF
Hasin
DS
Stinson
FS
, et al.  . 
The epidemiology of DSM-IV panic disorder and agoraphobia in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions
J Clin Psychiatry
 , 
2006
, vol. 
67
 (pg. 
363
-
374
)
42.
Tien
AY
Eaton
WW
Psychopathologic precursors and sociodemographic risk factors for the schizophrenia syndrome
Arch Gen Psychiatry
 , 
1992
, vol. 
49
 (pg. 
37
-
46
)
43.
Bermanzohn
PC
Arlow
PB
Pitch
RJ
Siris
SG
Panic and paranoia
J Clin Psychiatry
 , 
1997
, vol. 
58
 (pg. 
325
-
326
)
44.
Hofmann
SG
Relationship between panic and schizophrenia
Depress Anxiety
 , 
1999
, vol. 
9
 (pg. 
101
-
106
)
45.
Siris
SG
Mason
SE
Shuwall
MA
Histories of substance abuse, panic and suicidal ideation in schizophrenic patients with histories of post-psychotic depression
Prog Neuropsychopharmacol Biol Psychiatry
 , 
1993
, vol. 
17
 (pg. 
609
-
617
)
46.
Fialko
L
Freeman
D
Bebbington
P
, et al.  . 
Understanding suicidal ideation in psychosis: findings from the psychological prevention of relapse in psychosis (PRP) trial
Acta Psychiatr Scand
 , 
2006
, vol. 
114
 (pg. 
177
-
186
)
47.
Weissman
MM
Fyer
AJ
Haghighi
F
, et al.  . 
Potential panic disorder syndrome: clinical and genetic linkage evidence
Am J Med Genet
 , 
2000
, vol. 
96
 (pg. 
24
-
35
)
48.
Shi
J
Badner
JA
Gershon
ES
Liu
C
Allelic association of G72/G30 with schizophrenia and bipolar disorder: a comprehensive meta-analysis
Schizophr Res
 , 
2008
, vol. 
98
 (pg. 
89
-
97
)
49.
Morgan
C
Fisher
H
Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma—a critical review
Schizophr Bull
 , 
2007
, vol. 
33
 (pg. 
3
-
10
)
50.
Shaw
K
McFarlane
AC
Bookless
C
Air
T
The etiology of postpsychotic posttraumatic stress disorder following a psychotic episode
J Trauma Stress
 , 
2002
, vol. 
15
 (pg. 
39
-
46
)
51.
Kennedy
BL
Dhaliwal
N
Pedley
L
Sahner
C
Greenberg
R
Manshadi
MS
Post-traumatic stress disorder in subjects with schizophrenia and bipolar disorder
J Ky Med Assoc
 , 
2002
, vol. 
100
 (pg. 
395
-
399
)
52.
Frame
L
Morrison
AP
Causes of posttraumatic stress disorder in psychotic patients
Arch Gen Psychiatry
 , 
2001
, vol. 
58
 (pg. 
305
-
306
)
53.
McGorry
PD
Chanen
A
McCarthy
E
Van Riel
R
McKenzie
D
Singh
BS
Posttraumatic stress disorder following recent-onset psychosis. An unrecognized postpsychotic syndrome
J Nerv Ment Dis
 , 
1991
, vol. 
179
 (pg. 
253
-
258
)
54.
Shaw
K
McFarlane
A
Bookless
C
The phenomenology of traumatic reactions to psychotic illness
J Nerv Ment Dis
 , 
1997
, vol. 
185
 (pg. 
434
-
441
)
55.
Calhoun
PS
Stechuchak
KM
Strauss
J
Bosworth
HB
Marx
CE
Butterfield
MI
Interpersonal trauma, war zone exposure, and posttraumatic stress disorder among veterans with schizophrenia
Schizophr Res.
 , 
2007
, vol. 
91
 (pg. 
210
-
216
)
56.
Fan
X
Henderson
DC
Nguyen
DD
, et al.  . 
Posttraumatic stress disorder, cognitive function and quality of life in patients with schizophrenia
Psychiatry Res
 , 
2008
, vol. 
159
 (pg. 
140
-
146
)
57.
Gearon
JS
Kaltman
SI
Brown
C
Bellack
AS
Traumatic life events and PTSD among women with substance use disorders and schizophrenia
Psychiatr Serv
 , 
2003
, vol. 
54
 (pg. 
523
-
528
)
58.
Kilcommons
AM
Morrison
AP
Relationships between trauma and psychosis: an exploration of cognitive and dissociative factors
Acta Psychiatr Scand
 , 
2005
, vol. 
112
 (pg. 
351
-
359
)
59.
Meyer
H
Taiminen
T
Vuori
T
Aijälä
A
Helenius
H
Posttraumatic stress disorder symptoms related to psychosis and acute involuntary hospitalization in schizophrenic and delusional patients
J Nerv Ment Dis
 , 
1999
, vol. 
187
 (pg. 
343
-
352
)
60.
Mueser
KT
Goodman
LB
Trumbetta
SL
, et al.  . 
Trauma and posttraumatic stress disorder in severe mental illness
J Consult Clin Psychol
 , 
1998
, vol. 
66
 (pg. 
493
-
499
)
61.
Mueser
KT
Salyers
MP
Rosenberg
SD
, et al.  . 
5 Site Health and Risk Study Research Committee. Interpersonal trauma and posttraumatic stress disorder in patients with severe mental illness: demographic, clinical, and health correlates
Schizophr Bull.
 , 
2004
, vol. 
30
 (pg. 
45
-
57
)
62.
Neria
Y
Bromet
EJ
Sievers
S
Lavelle
J
Fochtmann
LJ
Trauma exposure and posttraumatic stress disorder in psychosis: findings from a first-admission cohort
J Consult Clin Psychol
 , 
2002
, vol. 
70
 (pg. 
246
-
251
)
63.
Priebe
S
Bröker
M
Gunkel
S
Involuntary admission and posttraumatic stress disorder symptoms in schizophrenia patients
Compr Psychiatry
 , 
1998
, vol. 
39
 (pg. 
220
-
224
)
64.
Resnick
SG
Bond
GR
Mueser
KT
Trauma and posttraumatic stress disorder in people with schizophrenia
J Abnorm Psychol
 , 
2003
, vol. 
112
 (pg. 
415
-
423
)
65.
Seedat
S
Fritelli
V
Oosthuizen
P
Emsley
RA
Stein
DJ
Measuring anxiety in patients with schizophrenia
J Nerv Ment Dis
 , 
2007
, vol. 
195
 (pg. 
320
-
324
)
66.
Strakowski
SM
Keck
PE
Jr
McElroy
SL
Lonczak
HS
West
SA
Chronology of comorbid and principal syndromes in first-episode psychosis
Compr Psychiatry
 , 
1995
, vol. 
36
 (pg. 
106
-
112
)
67.
Kessler
RC
Sonnega
A
Bromet
E
Hughes
M
Nelson
CB
Posttraumatic stress disorder in the National Comorbidity Survey
Arch Gen Psychiatry
 , 
1995
, vol. 
52
 (pg. 
1048
-
1060
)
68.
Strauss
JL
Calhoun
PS
Marx
CE
, et al.  . 
Comorbid posttraumatic stress disorder is associated with suicidality in male veterans with schizophrenia or schizoaffective disorder
Schizophr Res
 , 
2006
, vol. 
84
 (pg. 
165
-
169
)
69.
Calhoun
PS
Bosworth
HB
Stechuchak
KA
Strauss
J
Butterfield
MI
The impact of posttraumatic stress disorder on quality of life and health service utilization among veterans who have schizophrenia
J Trauma Stress
 , 
2006
, vol. 
19
 (pg. 
393
-
397
)
70.
Scheller-Gilkey
G
Moynes
K
Cooper
I
Kant
C
Miller
AH
Early life stress and PTSD symptoms in patients with comorbid schizophrenia and substance abuse
Schizophr Res
 , 
2004
, vol. 
69
 (pg. 
167
-
174
)
71.
Goodman
C
Finkel
B
Naser
M
, et al.  . 
Neurocognitive deterioration in elderly chronic schizophrenia patients with and without PTSD
J Nerv Ment Dis
 , 
2007
, vol. 
195
 (pg. 
415
-
420
)
72.
Berman
I
Kalinowski
A
Berman
SM
Lengua
J
Gren
AI
Obsessive and compulsive symptoms in chronic schizophrenia
Compr Psychiatry
 , 
1995
, vol. 
36
 (pg. 
6
-
10
)
73.
Eisen
JL
Beer
DA
Pato
MT
Venditto
TA
Rasmussen
SA
Obsessive-compulsive disorder in patients with schizophrenia or schizoaffective disorder
Am J Psychiatry
 , 
1997
, vol. 
154
 (pg. 
271
-
273
)
74.
Fabisch
K
Fabisch
H
Langs
G
Wieselmann
G
Zapotoczky
HG
Obsessive-compulsive symptoms in schizophrenia
Schizophr Res
 , 
1997
, vol. 
24
 pg. 
15
 
75.
Fabisch
K
Fabisch
H
Langs
G
Huber
HP
Zapotoczky
HG
Incidence of obsessive-compulsive phenomena in the course of acute schizophrenia and schizoaffective disorder
Schizophr Res
 , 
2001
, vol. 
16
 (pg. 
336
-
341
)
76.
Fenton
WS
McGlashan
TH
The prognostic significance of obsessive-compulsive symptoms in schizophrenia
Am J Psychiatry
 , 
1986
, vol. 
143
 (pg. 
437
-
441
)
77.
Karno
M
Golding
JM
Sorensen
SB
Burnam
MA
The epidemiology of obsessive-compulsive disorder in five US communities
Arch Gen Psychiatry
 , 
1988
, vol. 
45
 (pg. 
1094
-
1099
)
78.
Kayahan
B
Ozturk
O
Veznedaroglu
B
Eraslan
D
Obsessive-compulsive symptoms in schizophrenia: prevalence and clinical correlates
Psychiatry Clin Neurosci
 , 
2005
, vol. 
59
 (pg. 
291
-
295
)
79.
Krüger
S
Bräunig
P
Höffler
J
Shugar
G
Börner
I
Langkrär
J
Prevalence of obsessive-compulsive disorder in schizophrenia and significance of motor symptoms
J Neuropsychiatry Clin Neurosci
 , 
2000
, vol. 
12
 (pg. 
16
-
24
)
80.
Meghani
SR
Penick
EC
Nickel
EJ
Schizophrenia patients with and without OCD
Paper presented at: 151st Annual Meeting of the American Psychiatric Association
 , 
1998
Toronto, ON
81.
Mohammadi
MR
Ghanizadeh
A
Moini
R
Lifetime comorbidity of obsessive-compulsive disorder with psychiatric disorders in a community sample
Depress Anxiety
 , 
2007
, vol. 
24
 (pg. 
602
-
607
)
82.
Nechmad
A
Ratzoni
G
Poyurovsky
M
, et al.  . 
Obsessive-compulsive disorder in adolescent schizophrenia patients
Am J Psychiatry
 , 
2003
, vol. 
160
 (pg. 
1002
-
1004
)
83.
Porto
L
Bermanzohn
PC
Pollack
S
Morrissey
R
Siris
SG
A profile of obsessive-compulsive symptoms in schizophrenia
CNS Spectrum
 , 
1997
, vol. 
2
 (pg. 
21
-
25
)
84.
Poyurovsky
MD
Fuchs
C
Weizman
A
Obsessive-compulsive disorder in patients with first-episode schizophrenia
Am J Psychiatry
 , 
1999
, vol. 
156
 (pg. 
1998
-
2000
)
85.
Poyurovsky
M
Hramenkov
S
Isakov
V
Obsessive-compulsive disorder in hospitalized patients with chronic schizophrenia
Psychiatry Res
 , 
2001
, vol. 
102
 (pg. 
49
-
57
)
86.
Tibbo
P
Kroetsch
M
Chue
P
Warneke
L
Obsessive-compulsive disorder in schizophrenia
J Psychiatr Res.
 , 
2000
, vol. 
34
 (pg. 
139
-
146
)
87.
Tibbo
P
Warneke
L
Obsessive-compulsive disorder in schizophrenia: epidemiologic and biologic overlap
J Psychiatry Neurosci
 , 
1999
, vol. 
24
 (pg. 
15
-
24
)
88.
Lucka
I
Fryze
M
Cebella
A
Staszewsak
E
Prodromal symptoms of schizophrenics syndrome in children and adolescents
Psychiatr Pol
 , 
2002
, vol. 
36
 
suppl
(pg. 
283
-
286
)
89.
Iida
J
Iwasaka
H
Hirao
F
, et al.  . 
Clinical features of childhood-onset schizophrenia with obsessive-compulsive symptoms during the prodromal phase
Psychiatry Clin Neurosci
 , 
1995
, vol. 
49
 (pg. 
201
-
207
)
90.
Shioiri
T
Shinada
K
Kuwabara
H
Someya
T
Early prodromal symptoms and diagnoses before first psychotic episode in 219 inpatients with schizophrenia
Psychiatry Clin Neurosci
 , 
2007
, vol. 
61
 (pg. 
348
-
354
)
91.
Poyurovsky
M
Faragian
S
Shabeta
A
Kosov
A
Comparison of clinical characteristics, co-morbidity and pharmacotherapy in adolescent schizophrenia patients with and without obsessive-compulsive disorder
Psychiatry Res
 , 
2008
, vol. 
159
 (pg. 
133
-
139
)
92.
Poyurovsky
M
Fuchs
C
Faragian
S
, et al.  . 
Preferential aggregation of obsessive-compulsive spectrum disorders in schizophrenia patients with obsessive-compulsive disorder
Can J Psychiatry
 , 
2006
, vol. 
51
 (pg. 
746
-
754
)
93.
Rajkumar
RP
Reddy
YC
Kandavel
T
Clinical profile of “schizo-obsessive” disorder: a comparative study
Compr Psychiatry
 , 
2008
, vol. 
49
 (pg. 
262
-
268
)
94.
Berman
I
Merson
A
Viegner
B
Losonczy
MF
Pappas
D
Green
AI
Obsessions and compulsions as a distinct cluster of symptoms in schizophrenia: a neuropsychological study
J Nerv Ment Dis
 , 
1998
, vol. 
186
 (pg. 
150
-
156
)
95.
Whitney
KA
Fastenau
PS
Evans
JD
Lysaker
PH
Comparative neuropsychological function in obsessive-compulsive disorder and schizophrenia with and without obsessive-compulsive symptoms
Schizophr Res
 , 
2004
, vol. 
69
 (pg. 
75
-
83
)
96.
Sevincok
L
Akoglu
A
Kokcu
F
Suicidality in schizophrenia patients with and without obsessive-compulsive disorder
Schizophr Res
 , 
1002
, vol. 
90
 (pg. 
198
-
202
)
97.
Poyurovsky
M
Kriss
V
Weisman
G
, et al.  . 
Familial aggregation of schizophrenia-spectrum disorders and obsessive-compulsive associated disorders in schizophrenia probands with and without OCD
Am J Med Genet B Neuropsychiatr Genet
 , 
2005
, vol. 
133
 (pg. 
31
-
36
)
98.
Poyurovsky
M
Michaelovsky
E
Frisch
A
, et al.  . 
COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study
Neurosci Lett
 , 
2005
, vol. 
389
 (pg. 
21
-
24
)
99.
Bottas
A
Cooke
RG
Richter
MA
Comorbidity and pathophysiology of obsessive-compulsive disorder in schizophrenia: is there evidence for a schizo-obsessive subtype of schizophrenia?
J Psychiatry Neurosci
 , 
2005
, vol. 
30
 (pg. 
187
-
193
)
100.
Mahendran
R
Liew
E
Subramaniam
M
De novo emergence of obsessive-compulsive symptoms with atypical antipsychotics in asian patients with schizophrenia or schizoaffective disorder: a retrospective, cross-sectional study
J Clin Psychiatry
 , 
2007
, vol. 
68
 (pg. 
542
-
545
)
101.
Ertugrul
A
Anil Yagcioglu
AE
Eni
N
Yazici
KM
Obsessive-compulsive symptoms in clozapine-treated schizophrenic patients
Psychiatry Clin Neurosci
 , 
2005
, vol. 
59
 
2
(pg. 
219
-
22
)
102.
Tranulis
C
Potvin
S
Gourgue
M
Leblanc
G
Mancini-Marie
A
Stip
E
The paradox of quetiapine in obsessive-compulsive disorder
CNS Spectr
 , 
2005
, vol. 
10
 
5
(pg. 
356
-
61
)
103.
Lykouras
L
Alevizos
B
Michalopoulou
P
Rabavilas
A
Obsessive-compulsive symptoms induced by atypical antipsychotics. A review of the reported cases
Prog Neuropsychopharmacol Biol Psychiatry
 , 
2003
, vol. 
27
 
3
(pg. 
333
-
46
)
104.
Bloch
MH
Landeros-Weisenberger
A
Kelmendi
B
Coric
V
Bracken
MB
Leckman
JF
A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder
Mol Psychiatry
 , 
2006
, vol. 
11
 
7
(pg. 
622
-
32
)
105.
Denys
D
de Geus
F
van Megen
HJ
Westenberg
HG
A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors
J Clin Psychiatry
 , 
2004
, vol. 
65
 
8
(pg. 
1040
-
8
)
106.
Bystritsky
A
Ackerman
DL
Rosen
RM
Vapnik
T
Gorbis
E
Maidment
KM
Saxena
S
Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial
J Clin Psychiatry
 , 
2004
, vol. 
65
 
4
(pg. 
565
-
8
)
107.
Connor
KM
Payne
VM
Gadde
KM
Zhang
W
Davidson
JR
The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients
J Clin Psychiatry
 , 
2005
, vol. 
66
 
1
(pg. 
49
-
51
)
108.
Taylor
MA
Are schizophrenia and affective disorder related? A selective literature review
Am J Psychiatry
 , 
1992
, vol. 
149
 (pg. 
22
-
32
)
109.
Walker
J
Curtis
V
Murray
RM
Schizophrenia and bipolar disorder: similarities in pathogenic mechanisms but differences in neurodevelopment
Int Clin Psychopharmacol
 , 
2002
, vol. 
17
 
Suppl. 3
(pg. 
S11
-
19
)
110.
Ketter
TA
Wang
PW
Becker
OV
Nowakowska
C
Yang
Y
Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia?
J Psychiatr Res
 , 
2004
, vol. 
38
 (pg. 
47
-
61
)
111.
Craddock
N
O'Donovan
MC
Owen
MJ
Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology
Schizophr Bull
 , 
2006
, vol. 
32
 (pg. 
9
-
16
)
112.
Raymond Lake
C
Disorders of thought are severe mood disorders: the selective attention defect in mania challenges the Kraepelinian dichotomy a review
Schizophr Bull
 , 
2008
, vol. 
34
 (pg. 
109
-
117
)
113.
Moller
HJ
Occurrence and treatment of depressive comorbidity/cosyndromality in schizophrenic psychoses: conceptual and treatment issues
World J Biol Psychiatry
 , 
2005
, vol. 
6
 (pg. 
247
-
263
)
114.
Bartels
SJ
Drake
RE
Depressive symptoms in schizophrenia: comprehensive differential diagnosis
Compr Psychiatry
 , 
1988
, vol. 
29
 (pg. 
467
-
483
)
115.
Osby
U
Correia
N
Brandt
L
Ekbom
A
Sparen
P
Mortality and causes of death in schizophrenia in Stockholm county
Sweden. Schizophr Res
 , 
2000
, vol. 
45
 (pg. 
21
-
28
)
116.
Westermeyer
J
Comorbid schizophrenia and substance abuse: a review of epidemiology and course
Am J Addict
 , 
2006
, vol. 
15
 (pg. 
345
-
355
)
117.
Siris
SG
Adan
F
Cohen
M
Mandeli
J
Aronson
A
Casey
E
Postpsychotic depression and negative symptoms: an investigation of syndromal overlap
Am J Psychiatry
 , 
1988
, vol. 
145
 (pg. 
1532
-
1537
)
118.
Clarke
DM
Kissane
DW
Demoralization: its phenomenology and importance
Aust N Z J Psychiatry
 , 
2002
, vol. 
36
 (pg. 
733
-
742
)
119.
Kudo
J
Mori
H
Gomibuchi
T
Loneliness as expressed by schizophrenic patients in the early remission phase
Nagoya J Med Sci
 , 
2002
, vol. 
65
 (pg. 
115
-
126
)
120.
Roth
S
The seemingly ubiquitous depression following acute schizophrenic episodes, a neglected area of clinical discussion
Am J Psychiatry
 , 
1970
, vol. 
127
 (pg. 
51
-
58
)
121.
Knights
A
Hirsch
SR
“Revealed” Depression and drug treatment for schizophrenia
Arch Gen Psychiatry
 , 
1981
, vol. 
38
 (pg. 
806
-
811
)
122.
Baynes
D
Mulholland
C
Cooper
SJ
Montgomery
RC
, et al.  . 
Depressive symptoms in stable chronic schizophrenia: prevalence and relationship to psychopathology and treatment
Schizophr Res
 , 
2000
, vol. 
45
 (pg. 
47
-
56
)
123.
Herz
M
Prodromal symptoms and prevention of relapse in schizophrenia
J Clin Psychiatry
 , 
1985
, vol. 
46
 (pg. 
22
-
25
)
124.
Mandel
MR
Severe
JB
Schooler
NR
Gelenberg
AJ
Mieske
M
Development and prediction of postpsychotic depression in neuroleptic-treated schizophrenics
Arch Gen Psychiatry
 , 
1982
, vol. 
39
 (pg. 
197
-
203
)
125.
Johnson
DA
The significance of depression in the prediction of relapse in chronic schizophrenia
Br J Psychiatry
 , 
1988
, vol. 
152
 (pg. 
320
-
323
)
126.
Tsuang
D
Coryell
W
An 8-year follow-up of patients with DSM-III-R psychotic depression, schizoaffective disorder, and schizophrenia
Am J Psychiatry
 , 
1993
, vol. 
150
 (pg. 
1182
-
1188
)
127.
Sim
K
Chan
YH
Chong
SA
Siris
SG
A 24-month prospective outcome study of first-episode schizophrenia and schizoaffective disorder within an early psychosis intervention program
J Clin Psychiatry
 , 
2007
, vol. 
68
 (pg. 
1368
-
1376
)
128.
McGlashan
TH
Carpenter
WT
Jr
An investigation of the postpsychotic depressive syndrome
Am J Psychiatry
 , 
1976
, vol. 
133
 (pg. 
14
-
19
)
129.
Weissman
MM
Pottenger
M
Kleber
H
Ruben
HL
Williams
D
Thompson
WD
Symptom patterns in primary and secondary depression. A comparison of primary depressives with depressed opiate addicts, alcoholics, and schizophrenics
Arch Gen Psychiatry
 , 
1977
, vol. 
34
 (pg. 
854
-
862
)
130.
Van Putten
T
May
RP
“Akinetic depression” in schizophrenia
Arch Gen Psychiatry
 , 
1978
, vol. 
35
 (pg. 
1101
-
1107
)
131.
Knights
A
Okasha
MS
Salih
MA
Hirsch
SR
Depressive and extrapyramidal symptoms and clinical effects: a trial of fluphenazine versus flupenthixol in maintenance of schizophrenic out-patients
Br J Psychiatry
 , 
1979
, vol. 
135
 (pg. 
515
-
523
)
133.
Johnson
DA
Studies of depressive symptoms in schizophrenia
Br J Psychiatry
 , 
1981
, vol. 
139
 (pg. 
89
-
101
)
134.
Siris
SG
Harmon
GK
Endicott
J
Postpsychotic depressive symptoms in hospitalized schizophrenic patients
Arch Gen Psychiatry
 , 
1981
, vol. 
38
 (pg. 
1122
-
1123
)
135.
Roy
A
Depression in the course of chronic undifferentiated schizophrenia
Arch Gen Psychiatry
 , 
1981
, vol. 
38
 (pg. 
296
-
297
)
136.
Moller
HJ
von Zerssen
D
Depressive states occurring during the neuroleptic treatment of schizophrenia
Schizophr Bull
 , 
1982
, vol. 
8
 (pg. 
109
-
117
)
137.
Guze
SB
Cloninger
CR
Martin
RL
Clayton
PJ
A follow-up and family study of schizophrenia
Arch Gen Psychiatry
 , 
1983
, vol. 
40
 (pg. 
1273
-
1276
)
138.
Martin
RL
Cloninger
CR
Guze
SB
Clayton
PJ
Frequency and differential diagnosis of depressive syndromes in schizophrenia
J Clin Psychiatry
 , 
1985
, vol. 
46
 (pg. 
9
-
13
)
139.
Summers
F
Harrow
M
Westermeyer
J
Neurotic symptoms in the postacute phase of schizophrenia
J Nerv Ment Dis
 , 
1983
, vol. 
171
 (pg. 
216
-
221
)
140.
Roy
A
Depression, attempted suicide, and suicide in patients with chronic schizophrenia
Psychiatr Clin North Am
 , 
1986
, vol. 
9
 (pg. 
193
-
206
)
141.
Munro
JG
Hardiker
TM
Leonard
DP
The dexamethasone suppression test in residual schizophrenia with depression
Am J Psychiatry
 , 
1984
, vol. 
141
 (pg. 
250
-
252
)
142.
Elk
R
Dickman
BJ
Teggin
AF
Depression in schizophrenia: a study of prevalence and treatment
Br J Psychiatry
 , 
1986
, vol. 
149
 (pg. 
228
-
229
)
143.
Leff
J
Tress
K
Edwards
B
The clinical course of depressive symptoms in schizophrenia
Schizophr Res
 , 
1988
, vol. 
1
 (pg. 
25
-
30
)
144.
Johnson
DA
The significance of depression in the prediction of relapse in chronic schizophrenia
Br J Psychiatry
 , 
1988
, vol. 
152
 (pg. 
320
-
323
)
145.
Kulhara
P
Avasthi
A
Chadda
R
Chandiramani
K
Mattoo
SK
Kota
SK
Joseph
S
Negative and depressive symptoms in schizophrenia
Br J Psychiatry
 , 
1989
, vol. 
154
 (pg. 
207
-
211
)
146.
Hirsch
SR
Jolley
AG
The dysphoric syndrome in schizophrenia and its implications for relapse
Br J Psychiatry
 , 
1989
Suppl
(pg. 
46
-
50
)
147.
Barnes
TR
Curson
DA
Liddle
PF
Patel
M
The nature and prevalence of depression in chronic schizophrenic in-patients
Br J Psychiatry
 , 
1989
, vol. 
154
 (pg. 
486
-
491
)
148.
Bandelow
B
Muller
P
Gaebel
W
Kopcke
W
Linden
M
Muller-Spahn
F
Pietzcker
A
Reischies
FM
Tegeler
J
Depressive syndromes in schizophrenic patients after discharge from hospital. ANI Study Group Berlin, Dusseldorf, Gottingen, Munich
Eur Arch Psychiatry Clin Neurosci
 , 
1990
, vol. 
240
 (pg. 
113
-
120
)
149.
Addington
D
Addington
J
Depression dexamethasone nonsuppression and negative symptoms in schizophrenia
Can J Psychiatry
 , 
1990
, vol. 
35
 (pg. 
430
-
433
)
150.
Breier
A
Schreiber
JL
Dyer
J
Pickar
D
National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome
Arch Gen Psychiatry
 , 
1991
, vol. 
48
 (pg. 
239
-
246
)
151.
Lindenmayer
JP
Grochowski
S
Kay
SR
Schizophrenic patients with depression: psychopathological profiles and relationship with negative symptoms
Compr Psychiatry
 , 
1991
, vol. 
32
 (pg. 
528
-
533
)
152.
Birchwood
M
Mason
R
MacMillan
F
Healy
J
Depression, demoralization and control over psychotic illness: a comparison of depressed and non-depressed patients with a chronic psychosis
Psychol Med
 , 
1993
, vol. 
23
 (pg. 
387
-
395
)
153.
Koreen
AR
Siris
SG
Chakos
M
Alvir
J
Mayerhoff
D
Lieberman
J
Depression in first-episode schizophrenia
Am J Psychiatry
 , 
1993
, vol. 
150
 (pg. 
1643
-
1648
)
154.
Tapp
A
Tandon
R
Douglass
A
Dudley
E
Scholten
R
Underwood
M
Depression in severe chronic schizophrenia
Biol Psychiatry
 , 
1994
, vol. 
35
 pg. 
667
 
155.
Harrow
M
Yonan
CA
Sands
JR
Marengo
J
Depression in schizophrenia: are neuroleptics, akinesia, or anhedonia involved?
Schizophr Bull
 , 
1994
, vol. 
20
 (pg. 
327
-
338
)
156.
Mauri
MC
Bravin
S
Fabiano
L
Vanni
S
Boscati
L
Invernizzi
G
Depressive symptoms and schizophrenia a psychopharmacological approach
Encephale
 , 
1995
, vol. 
21
 (pg. 
555
-
558
)
157.
Markou
P
Depression in schizophrenia: a descriptive study
Aust N Z J Psychiatry
 , 
1996
, vol. 
30
 (pg. 
354
-
357
)
158.
Wassink
TH
Flaum
M
Nopoulos
P
Andreasen
NC
Prevalence of depressive symptoms early in the course of schizophrenia
Am J Psychiatry
 , 
1999
, vol. 
156
 (pg. 
315
-
316
)
159.
Muller
MJ
Wetzel
H
Dimensionality of depression in acute schizophrenia: a methodological study using the Bech-Rafaelsen Melancholia Scale (BRMES)
J Psychiatr Res
 , 
1998
, vol. 
32
 (pg. 
369
-
378
)
160.
Sands
JR
Harrow
M
Depression during the longitudinal course of schizophrenia
Schizophr Bull
 , 
1999
, vol. 
25
 (pg. 
157
-
171
)
161.
Zisook
S
McAdams
LA
Kuck
J
Harris
MJ
Bailey
A
Patterson
TL
Judd
LL
Jeste
DV
Depressive symptoms in schizophrenia
Am J Psychiatry
 , 
1999
, vol. 
156
 (pg. 
1736
-
1743
)
162.
Baynes
D
Mulholland
C
Cooper
SJ
Montgomery
RC
MacFlynn
G
Lynch
G
Kelly
C
King
DJ
Depressive symptoms in stable chronic schizophrenia: prevalence and relationship to psychopathology and treatment
Schizophr Res
 , 
2000
, vol. 
45
 (pg. 
47
-
56
)
163.
Bottlender
R
Strauss
A
Moller
HJ
Impact of duration of symptoms prior to first hospitalization on acute outcome in 998 schizophrenic patients
Schizophr Res
 , 
2000
, vol. 
44
 (pg. 
145
-
150
)
164.
Bressan
RA
Chaves
AC
Pilowsky
LS
Shirakawa
I
Mari
JJ
Depressive episodes in stable schizophrenia: critical evaluation of the DSM-IV and ICD-10 diagnostic criteria
Psychiatry Res
 , 
2003
, vol. 
117
 (pg. 
47
-
56
)
165.
Serretti
A
Mandelli
L
Lattuada
E
Smeraldi
E
Depressive syndrome in major psychoses: a study on 1351 subjects
Psychiatry Res
 , 
2004
, vol. 
127
 (pg. 
85
-
99
)
166.
Hafner
H
Maurer
K
Trendler
G
an der Heiden
W
Schmidt
M
Konnecke
R
Schizophrenia and depression: challenging the paradigm of two separate diseases–a controlled study of schizophrenia, depression and healthy controls
Schizophr Res
 , 
2005
, vol. 
77
 (pg. 
11
-
24
)
167.
Ohayon
MM
Schatzberg
AF
Prevalence of depressive episodes with psychotic features in the general population
Am J Psychiatry
 , 
2002
, vol. 
159
 (pg. 
1855
-
1861
)
168.
Johnson
J
Horwath
E
Weissman
MM
The validity of major depression with psychotic features based on a community study
Arch Gen Psychiatry
 , 
1991
, vol. 
48
 (pg. 
1075
-
1081
)
169.
Hafner
H
Maurer
K
Trendler
G
an der Heiden
W
Schmidt
M
Konnecke
R
Schizophrenia and depression: challenging the paradigm of two separate diseases–a controlled study of schizophrenia, depression and healthy controls
Schizophr Res
 , 
2005
, vol. 
77
 (pg. 
11
-
24
)
170.
Hafner
H
Loffler
W
Maurer
K
Hambrecht
M
an der Heiden
W
Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia
Acta Psychiatr Scand
 , 
1999
, vol. 
100
 (pg. 
105
-
118
)
171.
Yung
AR
Phillips
LJ
Yuen
HP
Francey
SM
McFarlane
CA
Hallgren
M
McGorry
PD
Psychosis prediction: 12-month follow up of a high-risk (“prodromal”) group
Schizophr Res
 , 
2003
, vol. 
60
 (pg. 
21
-
32
)
172.
Schothorst
PF
Emck
C
van Engeland
H
Characteristics of early psychosis
Compr Psychiatry
 , 
2006
, vol. 
47
 (pg. 
438
-
442
)
173.
Cornblatt
BA
Lencz
T
Smith
CW
Correll
CU
Auther
AM
Nakayama
E
The schizophrenia prodrome revisited: a neurodevelopmental perspective
Schizophr Bull
 , 
2003
, vol. 
29
 (pg. 
633
-
651
)
174.
Baxter
LR
Jr.
Schwartz
JM
Phelps
ME
Mazziotta
JC
Guze
BH
Selin
CE
Gerner
RH
Sumida
RM
Reduction of prefrontal cortex glucose metabolism common to three types of depression
Arch Gen Psychiatry
 , 
1989
, vol. 
46
 (pg. 
243
-
250
)
175.
Sackeim
HA
Prohovnik
I
Moeller
JR
Brown
RP
Apter
S
Prudic
J
Devanand
DP
Mukherjee
S
Regional cerebral blood flow in mood disorders. I. Comparison of major depressives and normal controls at rest
Arch Gen Psychiatry
 , 
1990
, vol. 
47
 (pg. 
60
-
70
)
176.
Berman
KF
Doran
AR
Pickar
D
Weinberger
DR
Is the mechanism of prefrontal hypofunction in depression the same as in schizophrenia? Regional cerebral blood flow during cognitive activation
Br J Psychiatry
 , 
1993
, vol. 
162
 (pg. 
183
-
192
)
177.
Barch
DM
Sheline
YI
Csernansky
JG
Snyder
AZ
Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression
Biol Psychiatry
 , 
2003
, vol. 
53
 (pg. 
376
-
384
)
178.
Campbell
S
Marriott
M
Nahmias
C
MacQueen
GM
Lower hippocampal volume in patients suffering from depression: a meta-analysis
Am J Psychiatry
 , 
2004
, vol. 
161
 (pg. 
598
-
607
)
179.
Videbech
P
Ravnkilde
B
Hippocampal volume and depression: a meta-analysis of MRI studies
Am J Psychiatry
 , 
2004
, vol. 
161
 (pg. 
1957
-
1966
)
180.
Honea
R
Crow
TJ
Passingham
D
Mackay
CE
Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies
Am J Psychiatry
 , 
2005
, vol. 
162
 (pg. 
2233
-
2245
)
181.
Boks
MP
Hoogendoorn
M
Jungerius
BJ
Bakker
SC
Sommer
IE
Sinke
RJ
Ophoff
RA
Kahn
RS
Do mood symptoms subdivide the schizophrenia phenotype? association of the GMP6A gene with a depression subgroup
Am J Med Genet B Neuropsychiatr Genet.
 , 
2007
182.
Drevets
WC
Neuroimaging abnormalities in the amygdala in mood disorders
Ann N Y Acad Sci
 , 
2003
, vol. 
985
 (pg. 
420
-
444
)
183.
Paradiso
S
Andreasen
NC
Crespo-Facorro
B
O'Leary
DS
Watkins
GL
Boles Ponto
LL
Hichwa
RD
Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography
Am J Psychiatry
 , 
2003
, vol. 
160
 (pg. 
1775
-
1783
)
184.
Siris
SG
Depression in schizophrenia: perspective in the era of “Atypical” antipsychotic agents
Am J Psychiatry
 , 
2000
, vol. 
157
 (pg. 
1379
-
1389
)
185.
Tollefson
GD
Sanger
Tm
Lu
Y
Thieme
ME
Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol
Arch Gen Psychiatry
 , 
1998
, vol. 
55
 
3
(pg. 
250
-
258
)
186.
Marder
SR
Davis
JM
Chouinard
G
The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials
J Clin Psychiatry
 , 
1997
, vol. 
58
 
12
(pg. 
538
-
546
)
187.
Emsley
R
Buckley
PF
Jones
AM
Greenwood
MR
Differential effect of quetiapine on depressive symptoms in patients with partially responsive schizophrenia
Journal of Psychopharmacology
 , 
2003
, vol. 
17
 
2
(pg. 
205
-
210
)
188.
Meltzer
Hy
Alphs
L
Green
AI
Altamura
C
ANad
R
Bertoldi
A
, et al.  . 
International suicide prevention trial study group. Clozapine treatment for suicidality in schizophrenia: International suicide prevention trial (InterSePT)
Arch Gen Psychiatry
 , 
2003
, vol. 
60
 
1
(pg. 
82
-
91
)
189.
Siris
SG
Morgan
V
Fagerstrom
R
Rifkin
A
Cooper
TB
Adjunctive imipramine in the treatment of postpsychotic depression. A controlled trial
Arch Gen Psychiatry
 , 
1987
, vol. 
44
 
6
(pg. 
533
-
539
)
190.
Cornblatt
BA
Lencz
T
Smith
CW
Olsen
R
Auther
AM
Nakayama
E
Lesser
ML
Tai
JY
Shah
MR
Foley
CA
Kane
JM
Correll
CU
Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents
J Clin Psychiatry
 , 
2007
, vol. 
68
 
4
(pg. 
546
-
57
)
191.
Regier
DA
Farmer
ME
Rae
DS
, et al.  . 
Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study
JAMA
 , 
1990
, vol. 
264
 (pg. 
2511
-
2518
)
192.
Kessler
RC
Crum
RM
Warner
LA
, et al.  . 
Lifetime co-occurrence of DSMIII-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Study
Arch Gen Psychiatry
 , 
1997
, vol. 
54
 (pg. 
313
-
321
)
193.
Merikangas
KR
Ames
M
Lui
L
The impact of comorbidity of mental and physical conditions on sole disability in the US adult household population
Arch Gen Psychiatry
 , 
2007
, vol. 
64
 
10
(pg. 
1180
-
1188
)
194.
O’ Daly
OG
Guillin
Tsapakis
EM
, et al.  . 
Schizophrenia and substance abuse comorbidity: a role for dopamine sensitization?
Journal of Dual Diagnosis
 , 
2005
, vol. 
1
 
2
(pg. 
11
-
40
)
195
Moore
TH
Zammit
S
Lingford-Hughes
A
, et al.  . 
Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review
Lancet
 , 
2007
, vol. 
370
 
95840
(pg. 
319
-
328
)
196.
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
, vol. 
325
 
7374
pg. 
1199
 
197.
Boydell
J
Dean
K
Dutta
R
, et al.  . 
A comparison of symptoms and family history in schizophrenia with and without prior cannabis use: implications for the concept of cvannabis psychosis
Schizophrenia Res
 , 
2007
, vol. 
93
 
1-3
(pg. 
203
-
210
)
198.
Caton
CL
Drake
RE
Hasin
DS
, et al.  . 
Differences between early-phase primary psychotic disorders with concurrent substance use and substance-induced psychoses
Arch Gen Psychiatry
 , 
2005
, vol. 
62
 
2
(pg. 
137
-
45
)
199.
Yucel
M
Solowij
N
Respondek
C
, et al.  . 
Regional brain abnormalities with long-term heavy cannabis use
Arch Gen Psychiatry
 , 
2008
, vol. 
65
 
6
(pg. 
694
-
701
)
200.
Chambers
RA
Bickel
WK
Potenza
MN
A scale-free systems theory of motivation and addiction
Neuroscj Biobehav Rev
 , 
2007
, vol. 
31
 (pg. 
1017
-
1045
)
201.
Dixon
L
Haas
G
Weiden
PJ
, et al.  . 
Acute effects of drug abuse in schizophrenic patients: clinical observations and patients’ self-reports
Schizophrenia Bulletin
 , 
1990
, vol. 
16
 (pg. 
69
-
79
)
202.
Voruganti
LNP
Heslegrave
RJ
Awad
AG
Neuroleptic dysphoria may be the missing link between schizophrenia and substance abuse
J Nerv Ment Dis
 , 
1997
, vol. 
185
 (pg. 
463
-
65
)
203.
Green
AI
Noordsy
DL
Burnette
MF
, et al.  . 
Substance abuse and schizophrenia: pharmacotherapeutic interventions
J Subst Abuse Treat
 , 
2008
, vol. 
34
 (pg. 
61
-
71
)
204.
Byerly
MJ
Nakonezny
PA
Lescouflair
E
Antipsychotic medication adherence in schizophrenia
Psych Clin North Am
 , 
2007
, vol. 
30
 
3
(pg. 
437
-
452
)
205.
Swartz
MS
Wagner
HR
Swanson
JW
, et al.  . 
The effectiveness of antipsychotic medications in patients who use or avoid illicit substances: Results from the CATIE study
Schizophr Res
 , 
2008
, vol. 
100
 
1-3
(pg. 
39
-
35
)
206.
Drake
RE
Xie
H
McHugo
GJ
, et al.  . 
The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia
Schizophrenia Bulletin
 , 
2000
, vol. 
26
 
2
(pg. 
441
-
9
)
207.
Cascade
E
Kalali
A
Buckley
PF
Current management of schizophrenia: antipsychotic monotherapy versus combination therapy
Psychiatry
 , 
2008
, vol. 
5
 
5
(pg. 
28
-
30
)