Psychiatric Annals

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Managing Depression in: Schizophrenia

Samuel G. Siris, MD

Abstract

Schizophrenia is a complex condition, and quite likely not a unitary one. Different patients meeting criteria for the schizophrenia diagnosis can and do exhibit different psychiatric symptoms. Indeed, the same patients can have different symptoms at different times. In that context, this article focuses on the topic of “depression” as it occurs in schizophrenia.

Depression itself is a term that is used with different meanings.1 The term “depression” can represent an affect, a symptom, a syndrome, or a disease. Watching a sad movie or hearing sad news, a person can experience depression as an affect. Such a reaction can be entirely appropriate to the situation and not in any way pathological. In contrast, an exaggerated or prolonged reaction of depression to a situation or reaction with depressed mood to a situation which does not call for it can be troubling to a person. In that context, the “depression” is a symptom.

When the symptom of depressed mood occurs together with certain other signs and symptoms (ie, anhedonia, sleep disturbance, appetite disturbance, reduced energy level, low self-esteem, pessimism, morbid thoughts, inability to concentrate, diminished confidence), we consider the picture of depression to be a syndrome. We also often speak about depression as disease, even though we lack definitive biological or tissue-level tests or criteria to make the diagnosis at that level. Indeed, even as we search for genes and explore other constructs appropriate to the concept of depression — and, for that matter, most other psychiatric disorders — as diseases, we must grapple with the possibility that they may be phenomena better conceptualized at the level of syndromes.

A medical example of a clinically relevant syndrome is fever. Although fever is a condition that could be diagnosed by a set of criteria, that causes suffering and dysfunction, that has a pathophysiology worthy of investigation and understanding, and that is remediable by specific treatments, it is not itself a disease. Rather, fever is a syndrome that can occur in various diseases. It nevertheless can cause people with it to appear “sick” in the same way.

Psychiatry's recent fascination with “bipolar depression” as somehow being the same, yet distinct, from other forms of depression can be understood in this same context.

Focusing on depression occurring in the context of patients who are also diagnosed as having schizophrenia is a worthy issue of our attention for several reasons. It is common; modal estimates are that depression occurs in 25% of patients with schizophrenia.2,3 It also is a source of substantial suffering and dysfunction, both in the patients themselves and in their families and communities, and is associated with a variety of unfortunate outcomes,4 including poor quality of life, cognitive problems, exacerbation of psychosis, rehospitalization, and increased cost of care. Finally, depression comorbid with schizophrenia? has been associated with increased risk of suicide attempts and completed suicides.5,6

An understanding of the etiology of the depression best informs the selection of a rational treatment strategy. The differential diagnosis of depression in schizophrenia includes medical and organic causes, acute and chronic disappointment reactions, other situational causes, a component of the prodrome of psychotic relapse, a phenotypic overlap with the symptoms of schizophrenia itself (positive, negative, cognitive, emotional discomfort, irritability), side effects of anti-psychotic medications, the possibility of an independent affective diathesis, and the presence of schizoaffective disorder.

The basis for this differential diagnosis, of course, depends on a comprehensive history and accurate understanding of the patient's symptomatology. The obtaining of these is, in turn, dependent on the clinician's skill in building rapport and creating a treatment alliance, and upon the clinician's ability to understand the often complicated…

Schizophrenia is a complex condition, and quite likely not a unitary one. Different patients meeting criteria for the schizophrenia diagnosis can and do exhibit different psychiatric symptoms. Indeed, the same patients can have different symptoms at different times. In that context, this article focuses on the topic of “depression” as it occurs in schizophrenia.

Defining Depression

Depression itself is a term that is used with different meanings.1 The term “depression” can represent an affect, a symptom, a syndrome, or a disease. Watching a sad movie or hearing sad news, a person can experience depression as an affect. Such a reaction can be entirely appropriate to the situation and not in any way pathological. In contrast, an exaggerated or prolonged reaction of depression to a situation or reaction with depressed mood to a situation which does not call for it can be troubling to a person. In that context, the “depression” is a symptom.

When the symptom of depressed mood occurs together with certain other signs and symptoms (ie, anhedonia, sleep disturbance, appetite disturbance, reduced energy level, low self-esteem, pessimism, morbid thoughts, inability to concentrate, diminished confidence), we consider the picture of depression to be a syndrome. We also often speak about depression as disease, even though we lack definitive biological or tissue-level tests or criteria to make the diagnosis at that level. Indeed, even as we search for genes and explore other constructs appropriate to the concept of depression — and, for that matter, most other psychiatric disorders — as diseases, we must grapple with the possibility that they may be phenomena better conceptualized at the level of syndromes.

A medical example of a clinically relevant syndrome is fever. Although fever is a condition that could be diagnosed by a set of criteria, that causes suffering and dysfunction, that has a pathophysiology worthy of investigation and understanding, and that is remediable by specific treatments, it is not itself a disease. Rather, fever is a syndrome that can occur in various diseases. It nevertheless can cause people with it to appear “sick” in the same way.

Psychiatry's recent fascination with “bipolar depression” as somehow being the same, yet distinct, from other forms of depression can be understood in this same context.

Depression in Schizophrenia

Focusing on depression occurring in the context of patients who are also diagnosed as having schizophrenia is a worthy issue of our attention for several reasons. It is common; modal estimates are that depression occurs in 25% of patients with schizophrenia.2,3 It also is a source of substantial suffering and dysfunction, both in the patients themselves and in their families and communities, and is associated with a variety of unfortunate outcomes,4 including poor quality of life, cognitive problems, exacerbation of psychosis, rehospitalization, and increased cost of care. Finally, depression comorbid with schizophrenia? has been associated with increased risk of suicide attempts and completed suicides.5,6

Differential Diagnosis

An understanding of the etiology of the depression best informs the selection of a rational treatment strategy. The differential diagnosis of depression in schizophrenia includes medical and organic causes, acute and chronic disappointment reactions, other situational causes, a component of the prodrome of psychotic relapse, a phenotypic overlap with the symptoms of schizophrenia itself (positive, negative, cognitive, emotional discomfort, irritability), side effects of anti-psychotic medications, the possibility of an independent affective diathesis, and the presence of schizoaffective disorder.

The basis for this differential diagnosis, of course, depends on a comprehensive history and accurate understanding of the patient's symptomatology. The obtaining of these is, in turn, dependent on the clinician's skill in building rapport and creating a treatment alliance, and upon the clinician's ability to understand the often complicated communications of a person suffering with a psychotic condition.

The first consideration in the differential diagnosis of depression in schizophrenia is whether the diagnosis of schizophrenia is correct. Psychotic mood disorders can present with depression and psychosis, and careful consideration needs to be given to that possibility. Substance-induced or other organically based psychotic episodes also can present with depressive symptoms, as can short-term acute psychotic episodes that do not meet durational criteria for schizophrenia. If the patient does not really have schizophrenia, the following discussion will, of course, have limited applicability. However, the considerations concerning the effects and side effects of antipsychotic agents may still have relevance.

Medical or Organic Etiologies

Numerous medical or organic causes can lead to depression-like symptomatology,7 and patients presenting with what appears to be depression in the course of schizophrenia merit a suitable medical work-up. Many central nervous system diseases can manifest depressive symptoms, including brain tumors, strokes, post-concussion syndromes, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, and HIV-associated dementia. Cardiovascular and pulmonary diseases including anemia, congestive heart disease, emphysema, and chronic bronchitis can create depressive sequelae, as can malignancies of various sorts, infectious diseases, and autoimmune disorders. Many metabolic and endocrine conditions, such as hypothyroidism, diabetes, liver failure, uremia, Addison's disease, Cushing's disease, and hypo- and hyperparathyroidism are known to produce a depression-like picture, as can severe malnutrition.

Medications used to treat medical conditions also can produce depressive symptoms as side effects, either in conjunction with their acute administration, in the course of long-term use, or at the time of their discontinuation.7 Familiar medications in these categories include sedative hypnotics, antihypertensive agents, estrogen or progesterone, steroids, sulfonamides, and various antineoplastic agents. Alcohol and drugs of abuse such as cocaine and amphetamines certainly can trigger depressive symptoms at times either of their acute use, chronic use, or discontinuation. It also is important to recognize that the discontinuation of either of the two most-used substances of all, nicotine and caffeine, can cause transient states lasting several days that can easily be confused with depression — a situation that can be especially relevant for patients entering units which are nicotine-free, caffeine-free, or both.

Acute Disappointment Reactions

It is part of the human condition that dysphoria accompanies the disappointment that occurs when events do not go well or results fall short of what had been hoped for. This mood bears many similarities to depressed mood: it may involve a component of loss or helplessness, it can be tinged with frustration, and it certainly is unpleasant. It is different from depression in that it is usually quite self-limited, its duration is relatively brief, and the relevant psychosocial event generally is easy to identify.

However, people with schizophrenia often have substantial deficits in interpersonal skills and have difficulty communicating effectively. They also can be quite vulnerable to symbolic or idiosyncratic disappointments that may not be apparent to other observers, and they can be susceptible to chains of non-Aristotelian logic, leading to unusual presumptions or convictions concerning the meaning and causality of events. Consequently, it is often crucial that the clinician be both skilled and sensitive in talking with the patient to identify the source or nature of the perceived disappointment. Occasionally, with support, understanding, and empathy, the disappointment reaction can be ameliorated directly or rectified by a suitable reinterpretation of the triggering circumstances. Even when this in not possible, non-specific support still may be useful in helping the patient ride out the stress without experiencing further harm. Acute disappointment reactions can occur in the context of acute psychosis as well, either in response to the unfolding of the episode of illness or in response to treatment interventions themselves. Patients may well be frustrated by the reemergence of positive psychotic symptoms or by other unpleasant or discouraging events that surround them. Such events can include separation from family, friends, and familiar places or things as a result of hospitalization in a relatively uncomfortable, unfamiliar, or even loathed setting in the company of strangers, labeled as “peers,” who often are themselves unhappy, frightened, or acting strangely.

Patients may further experience stigma from family, friends, or community members; it is hoped that this does not extend to professional psychiatric staff, although this can occur as well at times. They also find themselves treated as if they were children, unintelligent, or “bad” by people who misunderstand the nature of their illness. Such reactions by others can certainly erode the patient's confidence or self-esteem, further accentuating the phenocopy to depression in their clinical presentation.

Chronic Disappointment Reactions

Long-term disappointment reactions, also described as the “demoralization syndrome,” often are associated with a profound sense of powerlessness and have many features in common with depression.8 People with schizophrenia are prone to experience many disappointments that are not time-limited. They may have to face profound difficulties or even the impossibility of achieving important life goals in the realms of career, marriage, family, social life, or community recognition and acceptance. More personally, diminution of the capacity to concentrate, to think creatively, to communicate effectively, or to feel a part of the group may eat away at self esteem and morale. Loss of life roles may lead to loss of respect by others and loss of self-respect.

Any or all of these factors can lead to a quiet (or not so quiet) state of desperation or resignation that is difficult to distinguish from depression. This demoralization syndrome, however, may be particularly important to identify because it logically may be particularly responsive to specific rehabilitative, psychological, social, vocational, or environmental (eg, housing) interventions.

Depression as a Component of the Psychotic Prodrome

Depression-like symptoms, such as dysphoria, withdrawal, anhedonia, and sleep disturbances, often have been described as being part of the prodrome of new episodes of psychosis in schizophrenia.9 Whether these are an intrinsic component of the pathobiology of the illness is uncertain. They easily could represent the patient's psychological reaction to the unfolding of an unpleasant or ominous sequence of events.

Whatever their cause, these depression-like events are only diagnosable retrospectively, after psychotic symptoms have subsequently reemerged. Nevertheless, it is appropriate to recognize that a new emergence of depression in a patient with a history of schizophrenia might be a harbinger of the emergence of a new episode of psychosis, generally within a week or two. An appropriate treatment response for a new episode of depression in such a patient, therefore, is increased surveillance (especially with regard to psychotic or disinhibited symptomatology), ensuring adherence with antipsychotic medication regimens, interventions to reduce stress, and the bolstering of nonspecific psychosocial supports.

If these interventions are successful to the point where the incipient episode of psychosis is averted, it may then be impossible to differentiate what had just happened from an acute disappointment reaction. However, if a new episode of psychosis does emerge, the increased surveillance and supports will offer the best possible opportunity to limit its damage to the patient's life trajectory.

Phenotypic Overlap of Positive Symptoms With Depressive Symptoms

Some positive symptoms of psychosis resemble depressive symptoms directly. For example, agitation resembles psychomotor restlessness, catatonia and thought-blocking resemble psychomotor retardation, thought disorder and distractibility contribute to difficulties concentrating, and excitability or paranoia can present as sleep disturbances. Suicidal ideation has been associated with depressed mood in schizophrenia, but, interestingly it also has been associated with psychosis itself.10 Although some people certainly may turn to suicide because they are despondent, others with psychosis may opt for suicide as a means to escape feelings of being terrified, and still others may behave in risky ways on the basis of how disorganized or distracted they are.

In these cases, proper treatment of the psychosis would represent the best treatment for the depression-like picture as well. Indeed, specific “antidepressant” treatments of depression in schizophrenia only seem to be useful in those patients who are nonpsychotic or only residually psychotic, not in those who are floridly psychotic at the time of the intervention.3

Phenotypic Overlap of Negative Symptoms With Depressive Symptoms

Many negative symptoms of schizophrenia share phenomenological similarity to depression: anhedonia, lack of motivation, reduced energy level, diminished attentiveness, limited appetitive drives, and tendency for withdrawal. Features most useful in distinguishing depression from “negative” symptoms are blue mood (which is likely to be prominent in depression, whereas “flat” affect is typical for negative symptoms) and cognitive features of depression (eg, guilt, pessimism, ideas of worthlessness, suicidal notions). Negative symptoms also may be difficult to differentiate from akinesia (see next section).

Evidence has accumulated that “atypical” or second-generation antipsychotics (SGAs) have a more favorable spectrum of therapeutic action on negative symptoms than “standard” or first-generation antipsychotics (FGAs), especially over longer periods of time.1,11 If FGAs are used for patients with negative symptoms, it is useful to use the lowest possible doses that adequately control psychotic symptoms.

There is suggestive research that selective serotonin reuptake inhibitors (SSRIs) may be of value as adjunctive medications in patients with prominent negative symptoms.12 There is also limited evidence that tricyclic antidepressants, norepinephrine agonists, or dopamine agonists may be useful.13–15 Anticholinergic agents have also been proposed as treatments for negative symptoms, but whether they are of value for “true” negative symptoms or only those that are a component of neuroleptic-induced akinesia (see next section) remains to be demonstrated conclusively.16

Neuroleptic-induced akinesia

Akinesia is a side effect of dopamine-antagonist medication. It occurs as a result of dopamine blockade occurring in the basal ganglia. In its most easily recognizable presentation, it affects large muscles, leading to the typical Parkinsonian shuffling gait and lack of associated motor movements (such as reduced arm swing while walking), with muscle stiffness and cogwheel rigidity. More subtle manifestations of akinesia, which can occur in the absence of large muscle rigidity, and which can therefore more easily be confused with negative symptoms or depression in schizophrenia, can include stiffness of small muscle groups such as those of the face, leading to an expressionless or “dulled” appearance, or larynx, leading to “flattened” voice expressiveness during speech.

Another subtle manifestation of akinesia can be a general reduction in initiation or maintenance of motor behavior, leading to an overall nonspontaneous quality of action or interaction with others.17,18 The patient, of course, does not recognize the source of this nonspontaneity and may attribute it to “laziness” or “lack of willpower,” as people in the patient's environment may do as well. Blue mood often can accompany this form of akinesia,18 and it is easy to realize how such a presentation of akinesia can readily be mistaken for depression.

The fact that it is akinesia rather than depression is demonstrated by its prompt (usually within a couple of days to a week) response to antiparkinsonian medication in adequate doses. To achieve full response, treatment often may require 2 mg of oral benztropine three times per day or the equivalent — more if there are no side effects on that dose.

SGAs, known to have less in the way of extrapyramidal side effects than FGAs, are less likely to cause akinesia, but it has not been demonstrated that their occurrence with SGAs is impossible. Switching from an FGA to an SGA, however, certainly is one reasonable approach to the management of akinesia.

Neuroleptic-induced akathisia:

Another basal-ganglia–mediated side effect of neuroleptic medications is akathisia.19 As a form of general motor restlessness, it is in some ways a phenotypic opposite of akinesia. Commonly, akathisia presents with pacing or other obviously excessive motor activity that is easy to diagnose. However, akathisia also can occur in subtle forms, such as wandering, overtalkativeness, or subjective restlessness, that can be confounded with agitation or irritability. Because akathisia is an uncomfortable state that can be experienced as markedly dysphoric, it can be confused readily with depression, particularly in people who have difficulties or idiosyncrasies in the ways they express themselves. Akathisia is particularly problematic in that, perhaps in connection with the generalized propensity toward behavior it involves, it has been associated with suicide and suicide attempts.20 Although akathisia is not very likely to respond to anticholinergic antiparkinsonian medications, it often is responsive to lowering the dose of neuroleptic or the addition of a benzodiazepine or propranolol to the medication regimen.21

As is the case of akinesia, akathisia is less likely to present in the context of treatment with an SGA than it is with an FGA, although, again, its possibility cannot entirely be disregarded. Switching a patient from an FGA to an SGA is a rational approach to the treatment of akathisia.

Antipsychotic-induced dysphoria

The importance of dopamine in brain reward pathways22 supports the popular notion that neuroleptic medication commonly produces dysphoria as a side effect. The evidence from controlled studies of this issue, however, is mixed.23,24 The truth likely is that, at least with FGAs, some patients may be vulnerable to a dysphoric reaction during treatment. This can be minimized by treatment with the lowest effective dose.

A number of studies have found lower scores for depression in patients with schizophrenia who are treated with an SGA versus an FGA,1,11,25 although it is unclear whether this is because these SGAs cause less depression as a side effect than the comparison FGA (which has been haloperidol in most trials); because the SGAs are precipitating less extrapyramidal side effect activity that is being picked up as depression on rating scales; because the SGAs have some kind of intrinsic antidepressant quality of their own26 (superior to the possible intrinsic antidepressant activity of FGAs); or because of some combination of these reasons.1 It also may not be irrelevant to this discussion that treatment with the “prototypic” SGA, clozapine, has been noted to be associated with a much decreased incidence of suicide and suicide attempts in comparison with FGA treatment.27

Depression as a Component of the Schizophrenia Diathesis

Early descriptions of schizophrenia noted that these patients often had depression-like features, and more recent factor-analysis studies of this patient population commonly derive an axis of psychopathology along the dysphoria-depression-anxiety dimension. Depression, in this context, may therefore be intrinsic to schizophrenia and, of relevance to this, when depression has been measured in the context of the treatment of an acute psychotic episode in schizophrenia with antipsychotic agents (including studies using FGAs), the depression scores tend to ameliorate along with the psychosis scores during remission.3 Depression during the prodrome of psychotic episodes in schizophrenia also may be relevant to this. In these situations, treating the schizophrenia (eg, the psychotic diathesis) represents treating the depression as well, and nothing further needs to be done about it.

The place and definition of schizoaffective disorder in psychiatric nosology historically has been controversial. Arguments are made that schizoaffective disorder is a type of schizophrenia, a type of affective disorder, an independent entity that is neither schizophrenia nor an affective disorder, a subset of a continuum of mental disorders that runs from schizophrenia at one end to affective disorder at the other, or a category that is a political compromise with no meaningful biological basis.

Patients certainly exist, however, who meet the phenotypic criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),28 for schizoaffective disorder. In general, the suggested approach for such patient is to treat the psychosis first with antipsychotic agents because, very often, the depression dissipates when the psychosis comes under control.1,11 If depression lingers after the psychosis abates, or appears later in a patient at a nonpsychotic stage, it can be treated as a case of post-psychotic depression (see discussion below). Particularly in cases of the bipolar type of schizoaffective disorder, there may be a role for the co-use of mood stabilizers (eg, lithium or certain anticonvulsants) along with the antipsychotic medications in the treatment of depressive or other affective features.

Post-psychotic Depression

The term “post-psychotic depression” had been used in more than one context in the literature. Originally, it was considered a psychodynamic or psychosocial reaction to the psychosis that lingered on after the episode. Today, it appears as a purely descriptive item in the Appendix of DSM-IV,28 which gives its criteria as, in essence, an episode of major depression occurring in a patient who is, at the index time point, either nonpsychotic or only residually psychotic but who has had a previous episode diagnosable as schizophrenia (or schizoaffective disorder). Post-psychotic depression can occur immediately after the resolution of a psychotic episode, after a brief interval, or after an extended interval of the patient being nonpsychotic or only residually psychotic.

Most of the studies that have addressed the utility of adjunctive antidepressant medications added to ongoing antipsychotic treatment in post-psychotic depression have involved tricyclic antidepressants, and all the randomized double-blind controlled studies of adjunctive antidepressant medications in post-psychotic depression published to date have involved FGAs (or, at most, mixed populations of FGAs and SGAs), rather than a pure population treated with a single SGA.

Electroconvulsive therapy (ECT) has not been studied specifically in post-psychotic depression. As a group, although not all reviews agree entirely,29 most seem to suggest that adjunctive antidepressants can be of value to outpatients with syndromal presentations of post-psychotic depression who are being maintained on adequate treatment with antipsychotic medication.3,11,30,31 The one study of maintenance treatment with adjunctive antidepressants in this circumstance supports the notion that ongoing continuation with this treatment continues to be valuable and, if anything, fewer rather than more instances of psychotic exacerbation occur in patients receiving maintenance adjunctive antidepressant medication.32

Although, as noted, only a limited number of antipsychotic-antidepressant medication combinations have been investigated formally, studies have indicated that the use of a variety of such combinations for post-psychotic depression has become relatively widespread. Clinicians apparently are “voting with their prescription pads” in favor of the combinations, and also apparently not having experiences that have deterred them.33,34

Summary

A substantial number of patients who carry the diagnosis of schizophrenia, by contemporary criteria, also, for at least certain phases of their course, meet syndromal criteria for depression. This is relevant clinically not only because of the suffering and dysfunction involved but also because of the association of such depression with a number of adverse outcomes. The understanding and treatment of this syndrome can be approached from the standpoint of a differential diagnosis of its etiology. This differential diagnosis includes a variety of medical and organic etiologies, effects of the acute or chronic use of various medications or substances or of their discontinuation, acute or chronic disappointment reactions, situational reactions, the prodrome of a fresh psychotic episode, phenotypic expressions of positive or negative symptoms of schizophrenia, side effects to antipsychotic medications such as akinesia, akathisia, and direct mood effects, mood components of the schizophrenia diathesis itself, and the existence of a mood-disorder diathesis occurring independently from the patient's schizophrenia/psychosis diathesis. Substantial clinical expertise often is required in determining the correct diagnosis in light of the idiosyncrasies of logic or communication difficulties with which many schizophrenic patients present.

A correct differential diagnosis will suggest an appropriate treatment path, whether that be focused on concrete situational factors, the patient's psychological processes, or pharmacologic interventions. The availability of SGAs is, no doubt, a factor that opens up important useful options in the treatment or prevention of depression in schizophrenia, but their exact best roles, as well as the potential roles of newer antidepressant agents, remains to be worked out properly.

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Authors

Dr.Siris is professor of psychiatry, Albert Einstein College of Medicine, New York, NY, and director of the Division of Continuing Psychiatric Services for Schizophrenia and Related Conditions, The Zucker-Hillside Hospital, a component of the North Shore/Long Island Jewish Health System, Glen Oaks, NY.

Address reprint requests to: Samuel G. Siris, MD, The Zucker-Hillside Hospital, 75-59 263rd Street, Glen Oaks, New York 11004.

10.3928/00485713-20050101-08

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