It is generally accepted that the first building block of modern psychiatric nosology was Kraepelin's distinction between those disorders we now know as mood disorders and the illness (or illnesses) we now know as schizophrenia. Nevertheless, beginning with Bleuler (1911/1950), the observation was repeatedly made over the years that a substantial proportion of patients diagnosed with schizophrenia manifest some sort of "depressive-like" symptoms at certain points during their clinical course. These two propositions were difficult to reconcile because the Kraepelinian dichotomy maintained a powerful influence in psychiatry and empirical observations and understanding of the depressive state in patients with schizophrenia were slow to accumulate.
The seeming non sequitur of "depressive" symptoms in schizophrenia, as a consequence of Kraepelin's original observations, generated a tendency either to ignore or to psychologize depressive states in schizophrenia in the early and middle years of the 20th century. In some psychodynamic writings, the question of depression in schizophrenia was written off entirely on the basis of a thesis that schizophrenia patients, by definition, lacked the proper ego structures to develop depression. Elsewhere in the literature, psychodynamic formulations were used to explain states of depression in patients with schizophrenia. Meyer-Gross wrote about depression as being a reaction of despair to the psychotic process and a denial of the future (see McGlashan and Carpenter 1976b).
Other central psychodynamic themes included loss (Miller and Sonnenberg 1973; Roth 1970; Semrad 1966) and the notion that a state of depression was a necessary stage in the progression out of the more pathological narcissistic regressed 31 state that was represented by florid psychosis (Semrad 1966).
Semrad (1966) also understood the depressed state to be influenced by the pain and/or despair of an "empty ego." Both he and Eissler (1951), however, saw depression in schizophrenia as a moment of therapeutic opportunity, when insight and mastery might overcome more primitive defensive psychotic ego states as they receded.
A large number of medical/organic factors are possible as causes of depression in patients with schizophrenia (Bartels and Drake 1988). Obviously, any medical/organic factor that can lead to a depressive syndrome in an individual who does not have schizophrenia can also lead to a depressive state in a person with schizophrenia. Such possibilities include a number of common medical conditions (anemia, cancer, neurological disorders, infectious diseases, and metabolic or endocrine disorders), various medications used in the treatment of medical problems (antihypertensive medications such as beta-blockers, sedative-hypnotics, sulfonamides, and indomethacin), and discontinuation of other prescribed medications (most typically corticosteroids and psychostimulants).
Substances of abuse, such as alcohol, cannabis, cocaine, and narcotics, can contribute to phenocopies of depression on the basis of acute use, chronic use, or discontinuation. Importantly, the discontinuation of two "legal" substances very commonly used by schizophrenia patients--nicotine and caffeine--can lead to withdrawal states that can mimic depression (Lavin et al. 1996). In particular, "smoke-free" and "decaf" policies on many inpatient units can lead to diagnostic confusion unless the possibility of withdrawal symptoms is considered in the differential diagnosis of "depressive" states.
Negative Symptoms of Schizophrenia
Conceptually, the presentation of negative symptoms in patients with schizophrenia overlaps with the syndrome of depression in a number of domains (Andreasen and Olsen 1982; Bermanzohn and Siris 1992; Carpenter et al. 1985; Crow 1980; Siris et al. 1988a). Overlapping symptoms include poor energy, diminished interest, lack of pleasure, lowered drive state, reduced motor activity, impaired concentration, and general sense of helplessness. Other symptoms, however, may be helpful in making the distinction (Barnes et al. 1989; Kuck et al. 1992; Lindenmayer et al. 1991; Norman and Malla 1991). ....
More than two dozen studies have been published examining the rates of occurrence of depression in the course of schizophrenia (Koreen et al. 1993; Sands and Harrow 1999; Siris 1991, 1995; Tapp et al. 1994). They have varied considerably in terms of a number of methodological considerations: the definition employed for schizophrenia, the definition used for depression, the interval surveyed, the methodology of the survey, and the patients' treatment status at the time of the observation. The most notable conclusion that can be drawn from these studies is that, no matter what definitions and conditions prevail, at least some meaningful rate of phenotypic depression is observed in the course of schizophrenia.
Among these studies, the rates of depression varied from a low of 7% in a cross-sectional assessment of patients with DSM-III-defined schizophrenia who were chronically hospitalized and in whom an effort was made to distinguish depression from negative symptoms (Hirsch et al. 1989), to a high of 75% for at least one positive assessment of depression by either one of two criteria among patients with "first break" RDC-defined schizophrenia who were evaluated on a weekly to monthly basis for up to 5 years (Koreen et al. 1993). The modal rate for all these studies was 25%, a fair benchmark that has endured through the course of a number of reviews (Johnson 1981b; Mandel et al. 1982; McGlashan and Carpenter 1976b; Siris 1991, 1995; Winokur 1972).
Since depression is observed more frequently in females among people without schizophrenia (Kessler et al. 1993), and since the expression of schizophrenia in general is different in women than it is in men in a number of ways (Goldstein and Link 1988), it would be interesting to know if sex differences are observed with regard to the presentation of depression in patients with schizophrenia (Goldstein and Tsuang 1990; Seeman 1997). Indeed, such differences, if found, would have theoretical nosological implications ...
An appropriate treatment approach to depression begins with a consideration of the differential diagnostic possibilities outlined earlier in this chapter. Obviously, since there are no available biological tests (except for the medical/organic conditions), or even psychological tests, that are known to be informative in drawing these diagnostic distinctions, these diagnoses must be made on a purely clinical basis.
Figure 21 depicts an integrative schema that conceptualizes the interplay of extrinsic and intrinsic factors with the schizophrenia diathesis. The basis for this formulation is the familiar stress-diathesis model of schizophrenia (Nuechterlein and Dawson 1984; Zubin and Spring 1977), supported by more recent understanding of the neuropsychological underpinnings of the pathophysiology of schizophrenia (Weinberger 1987).
In Figure 21, the vertical axis represents vulnerability to psychotic symptoms of the schizophrenic type and the horizontal axis depicts the proportion of the general population. At the far left, a tiny fraction of the population manifests a very high vulnerability to psychosis, with an everdecreasing loading for such risk moving to the right along the curve.
Only a fraction of 1% of the population express a vulnerability so great that a schizophrenic psychosis will emerge under virtually any level of life stress, no matter how minor ...
Figure 21. Model of vulnerability, stress, and schizophrenic diathesis.
Addington D, Addington J, Patten S: Gender and affect in schizophrenia. Can J Psychiatry 41:265-268, 1996
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Washington, DC, American Psychiatric Association, 1994
Andreasen NC, Olsen S: Negative vs positive schizophrenia: definition and validation. Arch Gen Psychiatry 39:789-794, 1982
Atre-Vaidya N, Taylor MA: Effectiveness of lithium in schizophrenia: do we really have an answer? J Clin Psychiatry 50:170-173, 1989
Bandelow B, Muller P, Gaebel WE: Depressive syndromes in schizophrenic patients after discharge from hospital. Eur Arch Psychiatry Clin Neurosci 240:113-120, 1991
Barnes TR, Curson DA, Liddle PF, et al: The nature and prevalence of depression in chronic schizophrenic in-patients. Br J Psychiatry 154:486-491, 1989
Bartels SJ, Drake RE, McHugo GJ: Alcohol abuse, depression and suicidal behavior in schizophrenia. Am J Psychiatry 149:394-395, 1992
Becker RE: Implications of the efficacy of thiothixene and a chlorpromazineimipramine combination for depression in schizophrenia. Am J Psychiatry 140:208-211, 1983
Bermanzohn PC, Siris SG: Akinesia: A syndrome common to parkinsonism, retarded depression, and negative symptoms. Compr Psychiatry 33:221-232, 1992
Berrios GE, Bulbena A: Post psychotic depression: the Fulbourn cohort. Acta Psychiatr Scand 76:89-93, 1987
Birchwood M, Mason R, Macmillan F, et al: Depression, demoralization and control over psychotic illness: a comparison of depressed and non-depressed patients with a chronic psychosis. Psychol Med 23:387-395, 1993
Bland RC, Newman SC, Orn H: Schizophrenia: lifetime co-morbidity in a community sample. Acta Psychiatr Scand 75:383-391, 1987
Bleuler E: Dementia Praecox, or the Group of Schizophrenias (1911). New York, International Universities Press, 1950
Bodkin AJ, Cohen BM, Salomon MS, et al: Treatment of negative symptoms in schizophrenia and schizoaffective disorder by selegiline augmentation of antipsychotic medication. J Nerv Ment Dis 184:295-301, 1996
Bowers MD, Astrachan BM: Depression in acute schizophrenia. Am J Psychiatry 123:976-979, 1967
Bucci L: The negative symptoms of schizophrenia and the monoamine oxidase inhibitors. Psychopharmacology (Berl) 91:104-108, 1987
Caldwell CB, Gottesman II: Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophr Bull 16:571-589, 1990
Chien CP, DiMascio A, Cole JD: Antiparkinson agents and depot phenothiazines. Am J Psychiatry 131:86-90, 1984
Christison GW, Kirch DG, Wyatt RJ: When symptoms persist: choosing among alternative somatic treatments for schizophrenia. Schizophr Bull 17:217-240, 1991
Coryell W, Keller M, Lavori P, et al: Affective syndromes, psychotic features, and prognosis, I: depression. Arch Gen Psychiatry 47:651-657, 1990
Crow TJ: Molecular pathology of schizophrenia: more than one disease process? BMJ 280:66-68, 1980
Davis KL, Kahn RS, Ko G, et al: Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474-1486, 1991
DeAlarcon R, Carney MWP: Severe depressive mood changes following slowrelease intramuscular fluphenazine injection. BMJ 3:564-567, 1969
de Figueiredo JM: Depression and demoralization: phenomenologic differences and research perspectives. Compr Psychiatry 34:308-311, 1993
Docherty JP, van Kammen DP, Siris SG, et al: Stages of onset of acute schizophrenic psychosis. Am J Psychiatry 135:720-726, 1978
Drake RE, Cotton PG: Depression, hopelessness and suicide in chronic schizophrenia. Br J Psychiatry 148:554-559, 1986
Drake RE, Ehrlich J: Suicide attempts associated with akathisia. Am J Psychiatry 142:499-501, 1985
Dufresne RL, Kass DJ, Becker RE: Buproprion and thiothixene versus placebo and thiothixene in the treatment of depression in schizophrenia. Drug Development Research 12:259-266, 1988
Eissler KR: Remarks on the psycho-analysis of schizophrenia. Int J Psychoanal 32:139-156, 1951
Falloon I, Watt DC, Shepherd M: A comparative controlled trial of pimozide and fluphenazine decanoate in the continuation therapy of schizophrenia. Psychol Med 8:59-70, 1978
Fleischhaker WW, Roth SD, Kane JM: The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol 10:12-21, 1990
Floru L, Heinrich K, Wittek F: The problem of post-psychotic schizophrenic depressions and their pharmacological induction. International Pharmacopsychiatry 10:230-239, 1975
Frank JD: Persuasion and Healing. Baltimore, MD, Johns Hopkins University Press, 1973
Galdi J: The causality of depression in schizophrenia. Br J Psychiatry 142:621-625, 1983
Galdi J, Rieder RO, Silber D, et al: Genetic factors in the response to neuroleptics in schizophrenia: a pharmacogenetic study. Psychol Med 11:713-728, 1981
Goff DC, Midha KK, Sarid-Segal O, et al: A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology (Berl) 117:417-423, 1995
Goldstein JM, Link BG: Gender and the expression of schizophrenia. J Psychiatr Res 22:141-155, 1988
Goldstein JM, Tsuang MT: Gender and schizophrenia: an introduction and synthesis of findings. Schizophr Bull 16:179-183, 1990
Goldstein JM, Santangelo SL, Simpson JC, et al: The role of gender in identifying subtypes of schizophrenia: a latent class analytic approach. Schizophr Bull 16:263-275, 1990
Green MF, Nuechterlein KH, Ventura J, et al: The temporal relationship between depressive and psychotic symptoms in recent-onset schizophrenia. Am J Psychiatry 147:179-182, 1990
Haas GL, Glick ID, Clarkin JF, et al: Gender and schizophrenia outcome: a clinical trial of an inpatient family intervention. Schizophr Bull 16:277-292, 1990
Hafner H, Maurer K, Loffler W, et al: The epidemiology of early schizophrenia: influence of age and gender on onset and early course. Br J Psychiatry 164 (suppl 23):29-38, 1994
Hallonquist JD, Seeman MV, Lang M, et al: Variation in symptom severity over the menstrual cycle of schizophrenics. Biol Psychiatry 33:207-209, 1993
Halstead SM, Barnes TRE, Speller JC: Akathisia: prevalence and associated dysphoria in an in-patient population with chronic schizophrenia. Br J Psychiatry 164:177-183, 1994
Harrow M, Yonan CA, Sands JR, et al: Depression in schizophrenia: are neuroleptics, akinesia, or anhedonia involved? Schizophr Bull 20:327-338, 1994
Heilä H, Isometsä ET, Henriksson MM, et al: A nationwide psychological autopsy study on age- and sex-specific clinical characteristics of 92 suicide victims with schizophrenia. Am J Psychiatry 154:1235-1242, 1997
Herz M: Prodromal symptoms and prevention of relapse in schizophrenia. J Clin Psychiatry 46 (no 11, sec 2):22-25, 1985
Herz M, Melville C: Relapse in schizophrenia. Am J Psychiatry 137:801-805, 1980
Hirsch SR, Gaind R, Rohde PD, et al: Outpatient maintenance of chronic schizophrenic patients with long-acting fluphenazine: double-blind placebo trial. BMJ 1(854):633-637, 1973
Hirsch SR, Jolley AG, Barnes TRE, et al: Dysphoric and depressive symptoms in chronic schizophrenia. Schizophr Res 2:259-264, 1989
Hogarty GE, Munetz MR: Pharmacogenic depression among outpatient schizophrenic patients: a failure to substantiate. J Clin Psychopharmacol 4:17-24, 1984
Hogarty GE, Anderson CM, Reiss DJ, et al: Family psychoeducational, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia, 1: one-year effects of a controlled study on relapse and expressed emotion. Arch Gen Psychiatry 43:633-642, 1986
Johnson DAW: Depressions in schizophrenia: some observations on prevalence, etiology, and treatment. Acta Psychiatr Scand 63 (suppl 291):137-144, 1981a
Johnson DAW: Studies of depressive symptoms in schizophrenia. Br J Psychiatry 139:89-101, 1981b
Johnson DAW: The significance of depression in the prediction of relapse in chronic schizophrenia. Br J Psychiatry 152:320-323, 1988
Kessler RC, McGonagle KA, Swartz M, et al: Sex and depression in the National
Singh AN, Saxena B, Nelson HL: A controlled clinical study of trazodone in chronic schizophrenic patients with pronounced depressive symptomatology. Current Therapeutics Research 23:485-501, 1978
Siris SG: Akathisia and "acting-out." J Clin Psychiatry 46:395-397, 1985
Siris SG: Implications of normal brain development for the pathogenesis of schizophrenia (letter). Arch Gen Psychiatry 45:1055, 1988
Siris SG: Diagnosis of secondary depression in schizophrenia: implications for DSM-IV. Schizophr Bull 17:75-98, 1991
Siris SG: Depression and schizophrenia, in Schizophrenia. Edited by Hirsch SR, Weinberger DR. Cambridge, MA, Blackwell Science, 1995, pp 128-145
Siris SG: The treatment of schizoaffective disorder, in Current Psychiatric Therapy II. Edited by Dunner DL. Philadelphia, PA, WB Saunders, 1996, pp 196-201
Siris SG: Depression in schizophrenia: perspective in the era of "atypical" antipsychotic agents. Am J Psychiatry 157:1379-1389, 2000
Siris SG, Lavin MR: Schizoaffective disorder, schizophreniform disorder and acute psychotic disorder (including brief reactive psychosis), in Comprehensive Textbook of Psychiatry/VI, 6th Edition. Edited by Kaplan HI, Sadock BJ. Philadelphia, PA, Williams & Wilkins, 1995, pp 1019-1031
Siris SG, Morgan V, Fagerstrom R, et al: Adjunctive imipramine in the treatment of post-psychotic depression: a controlled trial. Arch Gen Psychiatry 44:533-539, 1987
Siris SG, Adan F, Cohen M, et al: Post-psychotic depression and negative symptoms: an investigation of syndromal overlap. Am J Psychiatry 145:1532-1537, 1988a
Siris SG, Strahan A, Mandeli J, et al: Fluphenazine decanoate dose and severity of depression in patients with post-psychotic depression. Schizophr Res 1:31-35, 1988b
Siris SG, Bermanzohn PC, Mason SE, et al: Maintenance imipramine therapy for secondary depression in schizophrenia: a controlled trial. Arch Gen Psychiatry 51:109-115, 1994
Spina E, DeDomenico P, Ruello C, et al: Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients. Int Clin Psychopharmacol 9:281-285, 1994
Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria: rationale and reliability. Arch Gen Psychiatry 35:773-782, 1978
Stephens JH, Richard P, McHugh PR: Suicide in patients hospitalized for schizophrenia: 1913-1940. J Nerv Ment Dis 187:10-14, 1999
Strian F, Heger R, Klicpera C: The time structure of depressive mood in schizophrenic patients. Acta Psychiatr Scand 65:66-73, 1982
Szymanski HV, Simon J, Gutterman N: Recovery from schizophrenic psychosis. Am J Psychiatry 140:335-338, 1983
Tapp A, Tandon R, Douglass A, et al: Depression in severe chronic schizophrenia. Biol Psychiatry 35:667, 1994
Taylor MA: Are schizophrenia and affective disorder related? A selective literature review. Am J Psychiatry 149:22-32, 1992
Tollefson GD, Andersen SW, Tran PV: The course of depressive symptoms in predicting relapse in schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone. Biol Psychiatry 46:365-373, 1999
Van Putten T: The many faces of akathisia. Compr Psychiatry 16:43-47, 1975
Van Putten T, May PRA: 'Akinetic depression' in schizophrenia. Arch Gen Psychiatry 35:1101-1107, 1978
Waehrens J, Gerlach J: Antidepressant drugs in anergic schizophrenia: a doubleblind cross-over study with maprotiline and placebo. Acta Psychiatr Scand 61:438-444, 1980
Weinberger DR: Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660-669, 1987
Winokur G: Family history studies, VIII: secondary depression is alive and well, and . . . Diseases of the Nervous System 33:94-99, 1972
Wise RA: Neuroleptics and operant behaviour: the anhedonia hypothesis. Behav Brain Sci 5:39-87, 1982
Wistedt B, Palmstierna T: Depressive symptoms in chronic schizophrenic patients after withdrawal of long-acting neuroleptics. J Clin Psychiatry 44:369-371, 1983
World Health Organization: International Classification of Diseases (ICD-10): Clinical Descriptions and Diagnostic Guidelines (draft of field trials). Geneva, World Health Organization, 1988
Zubin J, Spring B: Vulnerability: a new view of schizophrenia. J Abnorm Psychol 86: 103-126, 1977