Differential Diagnosis of Depression in the Course of Schizophrenia
Andrey Nailor, M.D.·Published 16 June 2009·10 min read
Key points
Medical/Organic Factors A large number of medical/organic factors are possible as causes of depression in patients with schizophrenia (Bartels and Drake 1988).
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.
Overlapping symptoms include poor energy, diminished interest, lack of pleasure, lowered drive state, reduced motor activity, impaired concentration, and general sense of helplessness.
Blunting of affect, of course, is a feature that is more suggestive of negative symptoms, whereas prominent blue mood, sense of guilt, and suicidal thoughts are more suggestive of depression.
Medical/Organic Factors 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).
Blunting of affect, of course, is a feature that is more suggestive of negative symptoms, whereas prominent blue mood, sense of guilt, and suicidal thoughts are more suggestive of depression. Unfortunately, the picture is not always clear, especially since patients with schizophrenia often lack the interpersonal skills and communication abilities necessary to make their own subjective states well known.
Neuroleptic-Induced Dysphoria Whether neuroleptic medications are "depressogenic" is an unresolved, though hotly debated, issue. Such an effect might be expected, on a theoretical basis, because dopamine synapses are involved in the brain pathways that medicate "reward" (Harrow et al. 1994; Wise 1982). Blocking of pleasure or reward by dopamine blockade, therefore, possibly could lead to anhedonia and a generalized state of depression. Indeed, one well-designed study found more anhedonia and depression in schizophrenia patients who were taking neuroleptics in the maintenance phase of treatment than in those who were not (Harrow et al. 1994).
Written and revised by
Andrey Nailor, M.D.
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This study built on a series of earlier, more anecdotal reports that implicated neuroleptics in the etiology of depression among schizophrenia patients (DeAlarcon and Carney 1969; Floru et al. 1975; Galdi 1983; Galdi et al. 1981; Johnson 1981a). The bulk of the controlled-study evidence, however, has tended to refute the proposition that appropriate doses of neuroleptic medication lead to the development of depressive states in individuals with schizophrenia (Knights and Hirsch 1981; Moller and von Zerssen 1986; Siris 1991, 2000). Three types of studies have been involved in this negative evidence. The first involved assessment of schizophrenia patients during the course of their treatment for acute episodes of psychosis.
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When the appropriate questions were asked, it was ascertained that the greatest levels of depressive symptoms corresponded to the times when the patients were most psychotic and that the symptoms tended to resolve, albeit sometimes at a slower rate, when the psychotic episode was treated with neuroleptic medication (Green et al. 1990; Hirsch et al. 1989; Knights and Hirsch 1981; Leff et al. 1988; Moller and von Zerssen 1982; Strian et al. 1982; Szymanski et al. 1983).
These observations therefore suggest that depressive symptoms that were present before the neuroleptic was administered actually decreased during the course of neuroleptic treatment. The second group of studies comprised those that compared the ongoing course of schizophrenia in patients who were treated with neuroleptic medications with the course in those who did not receive such treatment. The patients treated with neuroleptics were not found to demonstrate more depression (Hirsch et al. 1973, 1989; Hogarty and Munetz 1984; Wistedt and Palmstierna 1983).
The third group of studies involved comparisons of schizophrenia patients with and without depression, which failed to show any differences in neuroleptic doses or neuroleptic blood levels between the groups (Bandelow et al. 1991; Barnes et al. 1989; Berrios and Bulbena 1987; Roy 1984; Roy et al. 1983; Siris et al. 1988b). Finally, relevant to this issue, one popular hypothesis concerning the pathophysiology of schizophrenia is that schizophrenia represents a disorder of dopamine regulation (Davis et al. 1991).
Simply put, this conceptualization posits schizophrenia patients as being "brittle" in terms of their dopamine regulation-that is, being vulnerable to the occurrence of dopamine storms (psychosis) and dopamine droughts (negative symptoms). Within this framework it is easy to imagine how the administration of more than the minimum required amount of neuroleptic (dopamine-blocking) medication during relatively psychosis-free intervals could exacerbate negative symptoms, which, in turn, because they can present a close phenocopy of depression as noted earlier, can give the impression of neuroleptic-induced depression.
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Neuroleptic-Induced Akinesia The extrapyramidal side effect of neuroleptic-induced akinesia has had more than one definition in the literature, and this can be a confusing point. The original definition, and the one that is easiest to recognize, involves stiffness with cogwheel rigidity of large muscle groups, leading to typical parkinsonian posture, shuffling gait, and reduction of accessory motor movements (Chien et al. 1984).
These symptoms are gross, and the diagnosis of this type of akinesia is relatively easy. A later definition, originally formulated by Rifkin et al. (1975, 1978) and elaborated by Van Putten and May (1978), is more subtle but describes an equally debilitating condition (Bermanzohn and Siris 1992; Martin et al. 1985). This form of akinesia, also extrapyramidal in origin, involves a reduction in the basal ganglia's ability to initiate and sustain behavior. Patients with this form of akinesia may or may not have decreased accessory motor movements, but behaviorally they are "like bumps on a log" and act as if "their starter motor is broken." If they are watching television, for example, they are likely not to get up spontaneously and do something else at the end of the show they are watching. Rather, they are likely to "just sit."
In fact, if the condition is severe, they are likely not to even have the spontaneity to change the channel to find a show they like. They also appear to lack initiative socially-a problem that may be manifested by a lack of ordinary interpersonal behaviors such as starting conversations in appropriate situations. Blue mood has also been noted to accompany this state. Obviously, when asked about their condition, patients with this form of akinesia are likely to report anhedonia, self-blame, and the subjective state of lack of energy (a state easily confused with depression).
Indeed, it is unfortunate that a large proportion of the studies that have examined the incidence or treatment of depression in patients with schizophrenia have not appropriately considered the possibility of this form of akinesia as a confounding factor and controlled for it either by a reduction in neuroleptic dose or by concomitant administration of full doses of antiparkinsonian medications.
Neuroleptic-Induced Akathisia A second extrapyramidal neuroleptic side effect that is easy to diagnose in its blatant form but that in its more subtle form can easily be confused with depression is akathisia (Siris 1985; Van Putten 1975). In akathisia, it is "as if the patient's starter motor won't shut off." Prominent motor restlessness makes the blatant form of this side effect obvious. Subtle forms can be more difficult to recognize, manifesting as a more modest propensity for increased motor behavior, perhaps some degree of wandering or overtalkativeness, or more excessive behavioral responses in situations than otherwise would occur.
In some patients, this can appear to be agitation. Importantly, akathisia is often experienced by patients as substantially dysphoric (Halstead et al. 1994; Van Putten 1975), and, indeed, akathisia has been associated with both suicidal ideation and suicidal behavior (Drake and Ehrlich 1985; Shear et al. 1983). Like akinesia, akathisia is likely to respond to a lowering of the neuroleptic dosage, if that can be achieved. Akathisia is less likely to respond to antiparkinsonian medication, however, although it may respond to benzodiazepines or beta-blockers (Fleischhaker et al. 1990).
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Disappointment Reactions People with schizophrenia may easily have as much, if not more, to be disappointed about in the way in which their lives are progressing as individuals who do not have schizophrenia, and their interpersonal or communication difficulties may make it more difficult than it otherwise would be to distinguish this situation from depression at any given point in time. Acute disappointment reactions can be distinguished by the parallel history of a suitable recent event (if that can be elicited) and a transient course (seldom more than a few days to a couple weeks).
Chronic disappointment reactions are known as demoralization (de Figueiredo 1993; Frank 1973; Klein 1974) and can be more difficult to distinguish from depression. A chronic history of disappointment or failure can lead a person with schizophrenia to the conviction that a useful or satisfying life is impossible. Indeed, it has been empirically validated that schizophrenia patients who feel less of a sense of control regarding their illness are more likely to experience depression (Birchwood et al. 1993). Of course, it is also reasonable to believe that the demoralization state is worthy of diagnosis and understanding because it is particularly likely to be amenable to appropriate psychosocial interventions.
Prodrome of Psychotic Relapse Studies that have reviewed or examined the process of decompensation into psychotic episodes in schizophrenia often have noted symptoms common to depression to be manifest at these times (Docherty et al. 1978;
Green et al. 1990; Herz 1985; Herz and Melville 1980; Hirsch et al. 1989; Johnson 1988; Tollefson et al. 1999). Anxiety and withdrawal are frequent accompaniments of dysphoria in this situation, and signs or symptoms of early psychotic decompensation, such as hypervigilance or overinterpretation of events, may provide a valuable clue as to the true nature of the psychotic prodrome. Usually the depressed-appearing state is short-lived when it is a component of the psychotic prodrome, lasting for a couple days to a week, before more prominent and definitive symptoms of psychosis become manifest.
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Schizoaffective Depression Conceptually, the diagnosis of schizoaffective disorder pertains when the patient's presentation of the full depressive syndrome coincides with the florid psychotic syndrome in patients who also have been psychotic in the absence of an affective syndrome. This situation has been defined differently according to various diagnostic schemes (Coryell et al. 1990; Levitt and Tsuang 1988; Taylor 1992), the application of which can cause some variation in the exact boundary between "depression in schizophrenia" and "schizoaffective depression."
The diagnosis of schizoaffective disorder opens up a set of treatment options that may be valuable but that take us beyond the scope of the present chapter (Siris 1996; Siris and Lavin 1995). The issue of schizoaffective disorder, of course, also enters into the consideration of postpsychotic depression in schizophrenia, because postpsychotic depression occurs in schizoaffective disorder as well. There have been no specific studies of the latter situation; clinical trials have essentially collapsed the latter group of patients with the former under the assumption that the same interventions are applicable in these two circumstances.
Depression as the Expression of a Biological Diathesis in the Course of Schizophrenia Finally, after the other elements of the differential diagnosis noted earlier in this section have been ruled out, we are left with the possibility of a depression based on a biological diathesis occurring in an individual otherwise correctly diagnosed with schizophrenia. The determination of this issue, at least at the present time, is inexact, since there is no available direct biological way to ascertain the presence of a biological diathesis for depression-or, for that matter, schizophrenia. Specifically, there is no biopsy, electrical test, chemical test, radiological test, genetic marker, or even autopsy finding that can definitively establish such a psychiatric diagnosis.
Instead, we are limited to phenomenological descriptors and patients' own accounts of their subjective states in arriving at our diagnoses. Indeed, patients' responses to medications have frequently been used historically as validators for the symptom lists we have come to employ today to establish the boundaries of diagnoses such as depression and schizophrenia-a use of "predicate logic" that clinicians would readily recognize as flawed if they saw a patient using it to arrive at an important conclusion.
On the other hand, since clinicians are fundamentally interested in identifying the most sensible treatment for suffering dysfunctional individuals when they employ a diagnostic scheme, this approach has validity in that appropriate treatments may be suggested even if the logic might be flawed and the underlying biological assumptions might not be correct. The discussion of treatment issues that occurs later in this chapter certainly should be interpreted with this in mind.
Samuel G. Siris, M.D.
References
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
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