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
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 . 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
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 Schatzberg167
studied 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.