Psychiatric Annals

CLINICAL SUBTYPING OF SCHIZOPHRENIA 

The Influence of Depression on the Course, Functioning, and Treatment of Patients With Schizophrenia

Ellen S Herbener, PhD; Martin Harrow, PhD; James Sands, PhD

Abstract

A large proportion of patients with schizophrenia suffer from depression. Estimates of the prevalence of depression in patients with schizophrenia suggest general rates of approximately 25% to 35%1-3 and lifetime rates of approximately 60% to 80%.4 Factor analyses of symptoms in patients with schizophrenia have found that depression emerges as a significant separate factor during the course of illness.5 Individuals with schizophrenia are at heightened risk for depression compared with the general population, although the exact mechanism behind this relationship needs further clarification.

Studies of depression within schizophrenia have been complicated because some of the core symptoms of depression may be present in patients with schizophrenia for other reasons. For example, some negative symptoms (eg, psychomotor retardation and anhedonia) are also important features of depression. Additionally, differences in methods used may contribute to inconsistencies in the literature. For example, studies that rely on observational ratings alone may not elicit information about subjective states that are important for the diagnosis of depression. Some research has suggested that although patients who have schizophrenia may present with flat and unchanging affect, their internal experience may be different.6 Certain symptoms, specifically depressed feelings and suicidality, are likely to require direct inquiry of the patient's experience.

Bermanzohn and Siris7 noted that the distinction between negative symptoms and depressive symptoms is sometimes difficult, but that it was possible to distinguish between general motor slowing and depressive symptoms. Perenyi et al.8 found it possible to distinguish between negative symptoms and depressive symptoms in patients with schizophrenia, although they noted that there was inconsistency among their own and others' findings about specific types of symptoms that might be useful in this differentiation. Studies examining correlations among positive, negative, and depressive symptoms in patients with schizophrenia have typically noted a stronger relationship between positive symptoms and depression than between negative symptoms and depression.9"11 Thus, the distinction may be difficult at times, but typically appears to be possible when clinicians consider all types of depressive symptoms in their diagnostic assessments.

Another important confounding element is the possibility that neuroleptic medication may induce symptoms that are strong phenocopies of depressive symptoms. In a meta-analysis of the literature on this issue, Siris2 noted that two side effects of neuroleptics, akinesia and akathisia, can strongly mimic depressive symptoms. Harrow et al.12 proposed a mechanism for this effect, noting that by decreasing the availability of dopamine, neuroleptics may interfere with both motor and reward systems, which could result in anhedonia, akinesia, and akathisia. In a study assessing the relationship between depressive symptoms and the use of neuroleptics during 10 years of followup, Harrow et al.12 found that patients with schizophrenia who were receiving neuroleptics were more likely to show depressive syndromes than were patients with schizophrenia who were not receiving neuroleptics. This relationship was replicated across multiple follow-ups during the 10-year period.

The use of neuroleptic medication does appear to be an important factor that may contribute to depressive syndromes in some patients with schizophrenia. However, other factors also appear to contribute, and the literature is inconsistent on this issue. For example, Siris2 reported that the use of neuroleptics could not account for all or most cases of depression in patients with schizophrenia. He noted that, overall, a consistent percentage of patients have depressive episodes regardless of neuroleptic status, and that there is no clear relationship between dose of neuroleptic and depression.

The inconsistency in findings has stimulated further research on what individual differences between patients may contribute to depressive responses in those treated with neuroleptics. Bermanzohn and Siris7 found that certain patients, particularly those with a personal or family history of depression, were…

A large proportion of patients with schizophrenia suffer from depression. Estimates of the prevalence of depression in patients with schizophrenia suggest general rates of approximately 25% to 35%1-3 and lifetime rates of approximately 60% to 80%.4 Factor analyses of symptoms in patients with schizophrenia have found that depression emerges as a significant separate factor during the course of illness.5 Individuals with schizophrenia are at heightened risk for depression compared with the general population, although the exact mechanism behind this relationship needs further clarification.

Studies of depression within schizophrenia have been complicated because some of the core symptoms of depression may be present in patients with schizophrenia for other reasons. For example, some negative symptoms (eg, psychomotor retardation and anhedonia) are also important features of depression. Additionally, differences in methods used may contribute to inconsistencies in the literature. For example, studies that rely on observational ratings alone may not elicit information about subjective states that are important for the diagnosis of depression. Some research has suggested that although patients who have schizophrenia may present with flat and unchanging affect, their internal experience may be different.6 Certain symptoms, specifically depressed feelings and suicidality, are likely to require direct inquiry of the patient's experience.

Bermanzohn and Siris7 noted that the distinction between negative symptoms and depressive symptoms is sometimes difficult, but that it was possible to distinguish between general motor slowing and depressive symptoms. Perenyi et al.8 found it possible to distinguish between negative symptoms and depressive symptoms in patients with schizophrenia, although they noted that there was inconsistency among their own and others' findings about specific types of symptoms that might be useful in this differentiation. Studies examining correlations among positive, negative, and depressive symptoms in patients with schizophrenia have typically noted a stronger relationship between positive symptoms and depression than between negative symptoms and depression.9"11 Thus, the distinction may be difficult at times, but typically appears to be possible when clinicians consider all types of depressive symptoms in their diagnostic assessments.

Another important confounding element is the possibility that neuroleptic medication may induce symptoms that are strong phenocopies of depressive symptoms. In a meta-analysis of the literature on this issue, Siris2 noted that two side effects of neuroleptics, akinesia and akathisia, can strongly mimic depressive symptoms. Harrow et al.12 proposed a mechanism for this effect, noting that by decreasing the availability of dopamine, neuroleptics may interfere with both motor and reward systems, which could result in anhedonia, akinesia, and akathisia. In a study assessing the relationship between depressive symptoms and the use of neuroleptics during 10 years of followup, Harrow et al.12 found that patients with schizophrenia who were receiving neuroleptics were more likely to show depressive syndromes than were patients with schizophrenia who were not receiving neuroleptics. This relationship was replicated across multiple follow-ups during the 10-year period.

The use of neuroleptic medication does appear to be an important factor that may contribute to depressive syndromes in some patients with schizophrenia. However, other factors also appear to contribute, and the literature is inconsistent on this issue. For example, Siris2 reported that the use of neuroleptics could not account for all or most cases of depression in patients with schizophrenia. He noted that, overall, a consistent percentage of patients have depressive episodes regardless of neuroleptic status, and that there is no clear relationship between dose of neuroleptic and depression.

The inconsistency in findings has stimulated further research on what individual differences between patients may contribute to depressive responses in those treated with neuroleptics. Bermanzohn and Siris7 found that certain patients, particularly those with a personal or family history of depression, were prone to akinesia with subjective features when treated with neuroleptics. Thus, it may be that a certain subset of patients with schizophrenia with specific vulnerability to depression have a lower threshold for an akinetic response to neuroleptic medications.

Finally, it remains unclear whether the depression that occurs in patients who have schizophrenia is identical to that experienced by patients who do not have schizophrenia. Although individuals from both groups appear to meet diagnostic criteria for depression, it is unclear whether they may still differ in symptom presentation in important ways, or whether there may even be meaningful differences in patterns of depressive symptoms among patients who have schizophrenia. Further, the exact relationship between vulnerability to depression and vulnerability to psychosis is unclear, with some evidence in patients who have psychotic depression suggesting that there may be an interaction effect between the severity of depression and the vulnerability to psychosis.13

TEMPORAL COURSE OF DEPRESSIVE SYMPTOMS

There appear to be several different patterns of relationship between depression and psychotic exacerbations in patients who have schizophrenia. For a subset of patients who have schizophrenia, depressive symptoms appear to present concurrently with psychotic exacerbations and to resolve with psychotic remission. Studies focusing primarily on acute inpatient populations have noted significant correlations between decreases in psychotic symptoms and decreases in depressive symptoms.11,14'15

A number of studies have suggested that there may be an important distinction between those patients whose depressive symptoms remit with psychosis and those for whom depressive symptoms continue. It appears that those patients whose depression continues may have a poorer long-term prognosis or more severe illness.216 For example, Nakaya et al.16 found that although patients with schizophrenia who had depressive symptoms did not differ from patients who did not have depressive symptoms in severity of positive or negative symptoms at intake, those who continued to show depressive symptoms 8 to 9 weeks later also continued to show more severe positive and negative symptoms than did nondepressed patients. Further, antipsychotic treatment alone appears to be effective in decreasing both psychotic symptoms and depressive symptoms in some patients who have schizophrenia, but not in others.14

Overall, the data suggest that although depressive symptoms may be fairly common during acute psychotic breaks, there may be significant differences between patients with schizophrenia who show ongoing depression and patients with schizophrenia who show depression only during psychotic exacerbations. However, Shanfield et al.17 noted some complications with attempts to identify patients with depressive symptoms specifically at different phases of illness, and reported that depressive symptoms may not be noticed by clinicians until the more dramatic psychotic symptoms resolve. Thus, distinctions between patients with schizophrenia whose depressive symptoms primarily co-occur with acute exacerbations of psychosis and patients for whom depressive episodes are more persistent may be difficult.

The term post-psychotic depression refers to depressive episodes that occur immediately following a period of acute psychosis. Understanding of post-psychotic depression has typically been based on the idea that, as psychosis resolves, awareness of the significance of the illness for the individual's life plans results in depression. Consonant with this idea is the finding that, for a subset of patients, depression increases as awareness of symptoms improves.18 In some patients with schizophrenia, then, it may be that a psychotic break creates a significantly traumatic event to trigger a depressive episode, as well as increases vulnerability to recurrent depressions in a manner similar to that in individuals who do not have schizophrenia.

Another temporal pattern for depression in patients who have schizophrenia is a rather persistent course that appears somewhat independent of psychotic exacerbations. In patients with this pattern, factors that contribute to vulnerability to depression in the general population, such as stress and familial history of depression, appear to be at work. In a prospective longitudinal study, Ventura et al.19 found a significant relationship between stressful life events and depressive exacerbations in patients with schizophrenia, as well as between stressful life events and increases in psychosis. Physiologic mechanisms through which stressors elicit responses have been studied in patients with schizophrenia, and some data suggest that these patients may have particularly impaired responses to psychosocial stress, and particularly cumulative psychosocial stresses, due to maladaptive neuroendocrine responses.20

Familial history of affective illness may also contribute to vulnerability to depression in patients who have schizophrenia. Kendler and Hays21 found that patients with schizophrenia who had family members diagnosed with unipolar depression were significantly more likely to experience depression than were those without a family history of unipolar depression. Although Subotnik et al.22 did not find a significant relationship between a family history of affective illness and specific depressive episodes, they did find that patients with schizophrenia who had such a history had higher scores on depressive scales throughout the follow-up assessment, indicating a persistent low to moderate level of depression in these patients. Such chronic low levels of depression may be transmitted genetically and could contribute to vulnerability to full depressive episodes via personality, maladaptive coping, or Other factors.

Evidence for such an ongoing vulnerability to depressive episodes also comes from longitudinal work performed by Sands and Harrow.1 In their study of depression across a 7%-year period during the longitudinal course of schizophrenia, they found that some individuals with schizophrenia appeared particularly prone to depression and presented with depression at multiple assessment periods. In contrast, there appeared to be a subset of patients with schizophrenia who, during the 7½ years, did not show depression at any point in time.

EFFECT OF DEPRESSION ON CLINICAL COURSE AND FUNCTIONING

When the relationship between depression and schizophrenia was initially studied, it was generally indicated that affective features present in acutely psychotic patients who had schizophrenia were associated with a better prognosis.23,24 However, later data on the effect of depression on the functioning of patients who had schizophrenia suggested that it was associated with significant deficits. For example, longitudinal research has shown that patients with schizophrenia who have comorbid depression have poorer work functioning, less satisfaction with social functioning, and generally poorer global functioning compared with patients with schizophrenia who do not have depression.1 Tollefson and Anderson4 similarly found that depressed mood contributed as much as or more than positive and negative symptoms to quality-of-life assessments by patients with schizophrenia, and that this effect was particularly strong in the area of interpersonal relationships.

Although a diagnosis of schizophrenia alone is associated with significant deficits in social and work functioning, depressive symptoms appear to contribute to even further disability in these areas. Comorbid depression also appears to contribute additively to deficits in cognitive functioning in schizophrenia. Kohler et al.10 found that although both depressed and nondepressed patients who had schizophrenia showed deficits in many areas of cognitive functioning, patients who had comorbid depression showed an additional deficit in the area of attention-vigilance.

Siris2 addressed the inconsistency in findings about the prognostic meaning of depression by noting that clear distinctions were not made in early studies between patients who present with depression only during periods of psychotic exacerbations and patients who present with depression in a more persistent manner. Siris noted that several studies suggested that patients with schizophrenia who experience more persistent depression may be at particularly high risk for psychotic relapse and, further, that such a pattern of depression is correlated with other factors associated with a poor outcome (eg, poor premorbid adjustment and insidious onset of first psychotic episodes).

TREATMENT

One compelling reason to actively treat depression in patients who have schizophrenia is the strong relationship among psychosis, depression, and suicide in this group.25'28 It is estimated that 10% to 13% of individuals with schizophrenia commit suicide, a rate that is at least 6 times higher than that in the general population.29"31 Although depression is one factor contributing to suicide in schizophrenia, suicide is a behavioral event with many contributing factors, including discouragement over the discovery that schizophrenia may involve many chronic features.27 Heila et al.29 studied all suicides occurring in Finland between April 1, 1987, and March 31, 1988. They noted that nearly two-thirds of the individuals with schizophrenia who committed suicide during that time were suffering from depressive syndromes, but that only 13% of the group were prescribed antidepressant medication. Similarly, Sands and Harrow1 found that only 20% of the patients with schizophrenia in their longitudinal sample who met criteria for a full depressive syndrome were receiving antidepressant medication.

Although the need for effective treatment is clear, data on how to treat depressive symptoms effectively in patients who have schizophrenia are less clear, lust as the temporal relationship between psychotic features and depressive features appears to be significant for prognosis, it also appears that responsiveness to medications may differ between individuals. In a subset of patients with schizophrenia and depressive symptoms at the acute phase, effective treatment of psychotic symptoms simultaneously results in a decrease in depressive symptoms.14

Patients with schizophrenia whose depressive symptoms tend to occur at other phases of illness may benefit more from adjunctive antidepressant treatment, although the evidence is mixed. Some studies have suggested that antidepressant medications are effective at reducing affective distress in patients who have schizophrenia and depression.2'32"34 For example, Siris et al.34 found that patients with schizophrenia who were treated with Imipramine in addition to antipsychotic medication were slower to relapse than were patients with depression and schizophrenia who were not treated with antidepressant medication. These data suggest that treatment of depressive symptoms may help decrease significant responses to stress, and thus delay the onset of psychotic exacerbations.

However, some research has yielded negative findings for the influence of antidepressant medication in patients with schizophrenia,35"37 and at least one study has suggested that antidepressant medication may exacerbate other symptoms of schizophrenia.38 Supplemental medication with antidepressants has been problematic because of the potential for interactions with neuroleptic and anticholinergic medications34; thus, patients taking combinations of medications need to be monitored carefully. However, because a main problem with the joint administration of neuroleptics and antidepressants is the compounded anticholinergic side effects, specifically hypotension, new medications with lower anticholinergic effects may be a useful alternative for the treatment of comorbid psychosis and depression. For example, some of the atypical antipsychotics and some of the new selective serotonin reuptake inhibitor antidepressants have low anticholinergic effects, and thus may be a good combination for patients with schizophrenia who are suffering from comorbid psychosis and depression.

The use of some of the novel antipsychotic medications alone may also prove effective in treating some patients with schizophrenia who have comorbid depression. Specifically, some of the novel antipsychotics target serotoninergic and dopaminergic functioning, and in studies at multiple sites, the use of atypical antipsychotics has been associated with decreases in psychotic symptoms and depressive symptoms.31'39,40 Some of the new antipsychotics may also eventually be licensed for use directly as antidepressant or mood-stabilizing agents, suggesting that the particular neurotransmitter systems affected by these medications may contribute to symptoms in a variety of significant mental disorders.

Overall, regarding treatment, clinicians may often fail to assess for depression in patients with schizophrenia because many other factors, such as medication and negative symptoms, may make the differential diagnosis difficult. Clearly, however, patients who have schizophrenia and depression are at high risk for poorer functioning and more severe outcomes, and depressive symptoms should be assessed carefully in this population. There is evidence that the use of antidepressant medications can be helpful for these individuals.34 Some of the more potentially dangerous drug interaction effects may be avoided through the careful choice of both antipsychotic and antidepressant medications. Clinicians should consider using antidepressants or should consider whether atypical antipsychotics would be helpful for patients with schizophrenia who have co-occurring depression.

CONCLUSION

Although many patients with schizophrenia experience serious depressive episodes, detection and adequate treatment of depression in this population is relatively poor. This oversight is particularly significant because of the high rate of suicide associated with depression in individuals who have schizophrenia. Clinicians should ask patients who have schizophrenia about depressive symptoms to better diagnose this problem, and should consider the use of antidepressant medications, particularly for those patients whose depressive symptoms continue beyond periods of acute psychotic exacerbation. Clinicians are urged to carefully monitor information available on antipsychotic and antidepressant medications to identify the safest and most effective treatment for their patients.

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10.3928/0048-5713-20001001-10

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