Depression and anxiety
Several studies analysed the prevalence of anxiety and depression in RA patients
[4]. Of the patients studied using the
Depression Anxiety and Stress Scale (DASS) and the Hospital Anxiety and Depression
Scale (HADS), 13.5% had anxiety only; 6.4% depression only and
21.8% had both anxiety and depression [5]. In another study the global distress for RA patients was almost twice
as high as for the corresponding group from the general population. In a multiple
logistic regression analysis the health assessment questionnaire (HAQ) was
positively associated with global distress (odds ratio (OR) 3.63) while the visual
analogue scale (VAS) for global disease activity was positively associated with
symptoms of depression (OR 1.03). Female RA patients (OR 5.45) appear to have a
higher probability for experiencing corresponding symptoms, whereas patients over 60
years appear to have less anxiety than younger patients (OR 0.11) [6]. In addition, demographic and socioeconomic
aspects play a role in diagnosing a depressive disorder in RA patients [7].
A further study aimed to explore which factors are associated with self-reported
anxiety and depression in Spondyloarthritis (SpA) patients. 3,711 patients from the
SpAScania cohort were sent a postal questionnaire to assess health-related quality
of life (HRQoL) and physical and mental functioning. In total, 683 (32%)
cases were classified as “possible anxiety” and 305 (14%) as
“possible depression” cases with mean (SD) HADS-A 5.9 (4.3) and
HADS-D 4.4 (3.6). There were no differences among the SpA subtypes in HADS-A and
HADS-D. HADS-A and HADS-D were associated with lower education, lower physical
activity (HADS-D only), chronic pain problems, more fatigue, lower general health,
lower HRQoL, lower level of functioning, higher disease activity, and lower
self-efficacy. Associations with anxiety and/or depression appear
multifactorial in patients with SpA including both personal and disease-related
factors [8]. Another nationwide
population-based retrospective cohort study was performed to analyze the
relationship between ankylosing spondylitis (AS) and the subsequent development of
psychiatric disorders. The AS cohort from in the Taiwan National Health Insurance
(NHI) Research Database consisted of 2331 patients being compared to matched control
patients without AS. The adjusted HR for depressive and anxiety disorders in
subjects with AS were significantly higher than those of the controls during follow
up [9].
Depression and anxiety are common neuropsychiatric complaints in SLE patients. The
prevalence of anxiety and depression varies substantially between studies due to
methodological limitations, heterogeneity in defining anxiety and depression,
patient selection, and metrics used. Moreover, there is a lack of studies evaluating
the validity, reliability, and interpretability of commonly used screening tools for
depression and anxiety in SLE patients [10].
Further comparative analysis of incidence and structure of anxiety-depressive
spectrum disorders in patients with various rheumatic diseases was performed.
Screening of depressive disorders (HADS-D≥8) was positive in 29.4%
patients, ranging from 41% in SLE to 20% in Behcetʼs disease (BD)
and primary Sjögrenʼs syndrome. Anxiety disorders (HADS-A≥8) was
diagnosed in 44.4% of the patients, ranging from 52% in RA patients
38% in BD [11].
Using Taiwan’s National Health Insurance Research Database, patients with
newly diagnosed primary Sjögren’s syndrome (pSS) were compared with
controls and newly diagnosed RA patients. Patients with pSS exhibited a
significantly higher risk of developing a depressive disorder (adjusted incidence
rate ratio [aIRR]=2.11, p<0.001) and an anxiety disorder
(aIRR=2.20, p<0.001) when compared with the non-pSS cohort as well
as with the RA patients. In particular female patients were found to be at greater
risk for developing these comorbidities [12].
Depression is recognized as a risk factor for the development of suicidal behavior. A
metaanalysis of 34 studies revealed that both suicidal ideation and completed
suicide seems to be more frequent in patients experiencing SLE, fibromyalgia and
arthritis. Major determinants were comorbid depression in fibromyalgia and
arthritis, and neuropsychiatric disease in SLE [13]. Another metaanalysis of 48 studies in SSc patients demonstrated that
negative emotions have very high levels in these patients, compared to both healthy
population other chronic rheumatic patients assessed with the same instruments and
cutoffs. Depression has been the most widely studied psychiatric comorbidity in
systemic sclerosis, followed by anxiety. Despite the fact that anger is a common
emotion in these diseases, it is poorly studied. Methodologic issues limited the
ability to draw strong conclusions from studies of predictors. Disease-specific
symptoms (swollen joints, gastrointestinal and respiratory symptoms and digital
ulcers) and factors related to physical appearance were associated with negative
emotions [14].
Bipolar Disorder
Recent data suggests that patients with rheumatic diseases have increased prevalence
of bipolar disorder (BD). The risk of developing BD was significantly higher among
patients with RA compared to individuals without RA with a pooled relative risk of
2.06 (95% confidence interval [CI], 1.34–3.17) [15]. A case-control study of 11,782 patients
with RA and 57,973 age- and gender-matched controls revealed that the prevalence of
BD in RA patients was increased (0.6 and 0.4%, respectively,
p=0.036) [16]. Moreover, another study
of a RA cohort from Taiwan demonstrated that the BD incidence was higher in patients
with RA (incidence rate ratio (IRR) 2.13, 95% CI 1.12–4.24,
P=.013) than in control patients [17].
Otherwise, there are some data for the differential response of BD patients diagnosed
with firromyalgia syndroms (FM) to standard therapies, taking into account the
markedly statistically significant increase of its prevalence in the syndrome. Ten
percent of 100 most recent FM consultations included patients with an established
diagnosis of BD. They had little if no response to traditional FM interventions and
appeared to have vague and uncertain tender point examinations. The authors conclude
that BD may be associated with a form of chronic musculoskeletal pain complaints
that is not FM [18]. One study aims to explore
the association between BD and the risk of gout using a nationwide population-based
dataset from Taiwan National Health Insurance Research Database. Gout occurred in
16.4% of the BD patients. After adjusting for potential confounders, the
regression analysis showed that the hazard of developing gout during the 6-year
follow-up period was 1.19 increased (95% CI 1.10–1.24,
P<0.001) for BD patients than their counterparts in the comparison cohort
[19].
Schizophrenia
Previous studies have documented reduced rates of RA in schizophrenia (SZ) [20]. In one population study from Manitoba,
Canada, the incidence and prevalence of SZ was studied in a population-based cohort
demonstrating that there was no difference between RA patients and the control group
[21]. Moreover, several studies have shown
that SZ has a protective effect on RA, with RA occurring less frequently in SZ cases
than would be expected by chance, whilst other studies have failed to replicate
this. Meta-analysis across studies over the past half-century showed that prevalence
of RA in SZ cases was significantly reduced (OR=0.48, 95% CI:
0.34–0.67, p<0.0001) [22].
Another population-based study included every individual identified in the Swedish
Population Register born in Sweden between 1932 and 1989. The risk for RA in SZ was
significantly decreased (hazard ratio [HR]=0.69, 95%
CI=0.59–0.80), but similar reductions were noted for osteoarthritis
(a noninflammatory joint disorder) and AS. Overall, first-degree relatives of SZ
patients were not at reduced risk of RA, but the risk for seronegative RA was
significantly decreased in children and siblings of SZ probands (HR=0.13,
95% CI=0.02–0.95 and HR=0.67, 95%
CI=049–0.92, respectively). The analyses indicated the possibility
of an inverse coinheritance of schizophrenia and seronegative RA [23] ([Tab.
1]).
The purpose of another study was to determine if a history of autoimmune diseases
(AD) is associated with an increased risk of later onset of SZ. Taiwan’s
National Health Insurance Research Database was used to identify a total of 64,817
AD patients and an equal number of age-matched control patients. The main finding
was the discovery of a higher incidence of subsequent SZ in patients with AD (HR
1.72, 95% CI 1.23–2.4) after adjustment for other demographic
characteristics. Specifically, the risk of SZ was observed to be significant
increased in SLE (3.73, 95% CI 2.07–6.72), dermatomyositis (5.85,
1.32–25.94) and autoimmune vasculitis (2.44, 1.17–5.06). In
addition, this study revealed some potential risk factors for developing SZ,
including younger age (less than or equal to 50 years) and some comorbidities
(hypertension, chronic obstructive pulmonary disease, and alcohol use disorder)
[24].
Table 1 Incidence und prevalence of psychiatric comorbidities
in patients with rheumatic diseases [5]
[10]
[16]
[21]
[22].
|
Incidence rate ratio
|
Prevalence (%)
|
|
depression
|
1.46 [95% CI) 1.35–1.58]
|
13.5–29.4
|
|
anxiety disorder
|
1.24 [95% CI 1.15–1.34]
|
6.4–44.4
|
|
bipolar disorder
|
1.21 [95% CI 1.00–1.47]
|
0.6
|
|
schizophrenia
|
0.48 [95% CI: 0.34–0.67]
|
0.25
|
Inflammation
Inflammation seems to play a role in the pathophysiology of mood disorders. In recent
years, several studies have shown increased levels of inflammatory and/or
immune markers in patients with mood disorders [25]. Moreover, there is cumulating evidence suggesting potential roles of
inflammatory cytokines in the pathogenesis of psychiatric disorders [26]. To clarify findings of elevated cytokine
levels in depression, one study aimed to investigate the relationship between serum
levels of cytokines, symptoms of depression and antidepressant treatment outcome. At
baseline (T0) and 4 weeks following initiation of antidepressant treatment (T1),
levels of various cytokines, CRP and depression ratings (Beck Depression Inventory -
II) were assessed in patients with major depression and age-and sex-matched
controls. The authors conclude that cytokines are not generally pro-depressive but
rather relate to a more specific regulation of symptoms and severity in depression
[27].
Otherwise, it was shown that pro- and anti-inflammatory cytokines mediate indoleamine
2,3-dioxygenase activity; this enzyme drives metabolism of tryptophan and kynurenine
in the central nervous system and degrades serotonin. Alterations of serotonergic,
noradrenergic, and glutamatergic neurotransmission have been associated with
low-level neuroinflammation, and anti-inflammatory compounds have a therapeutic
benefit in major depression and SZ, as shown in meta-analyses [28]. The novel treatment of autoimmune diseases
with cytokine-blockers presents a unique strategy to understand the role of
cytokines in affective disorder
Genetic association between rheumatic diseases and psychiatric
comorbidities
Genome-wide association studies in SZ and RA indicate genetic correlations,
suggesting that there may be shared pathogenesis at the DNA level or downstream.
Single nucleotide polymorphisms that conferred risk for both groups were
localized solely to the extended HLA region. Among single nucleotide
polymorphisms that conferred differential risk for SZ and RA, the majority were
localized to HLA-B, TNXB, NOTCH4, HLA-C,
HCP5, MICB, PSORS1C1, and C6orf10. Published
functional data indicate that HLA-B and HLA-C have the most plausible pathogenic
roles in both disorders. The genes harboring apparently pleiotropic single
nucleotide polymorphisms are closely connected to RA and SZ associated genes
through common interacting partners. A separate and independent analysis of the
interactomes of RA and SZ genes showed a significant overlap between the 2
interactomes sharing several common pathways [3]. Furthermore, advances in understanding the genetic basis of RA
have shown that much of the genetic liability to this condition is due to risk
and protective alleles at the HLA DRB1 locus. These data allow robust testing of
the hypotheses that allelic variation at DRB1 pleiotropically modulates the risk
of RA and SZ. A systematic review of the literature indicates associations of
DRB1 variants: DRB1*04 alleles have been associated with increased risk
of RA and autism but decreased risk of SZ, and DRB1*13 alleles have been
associated with protection from RA and autism but higher risk of SZ [29] . On the other hand, meta-analysis of
genome-wide association studies to investigate the shared association loci
between RA and SZ at the genome-wide scale showed a significant peak at the
major histocompatibility complex (MHC) locus on chromosome 6 in both RA and SZ.
Testing RA- and SZ-associated loci outside the human leukocyte antigen region
showed no association with both RA and SZ. The findings are consistent with the
role of MHC locus in the genetic correlation between RA and SZ, and suggest that
either SZ has an autoimmune basis and/or RA has an active neurological
component [30]. The genomics era presents
an alternative paradigm for investigating the genetic relationship between 2
uncommon disorders. A study tested genome-wide common single nucleotide
polymorphism (SNP) data from independently collected SZ and RA case-control
cohorts to estimate the SNP correlation between the disorders. They utilized a
genotype X environment (GxE) hypothesis for SZ with environment defined as
winter- vs summer-born. The results are consistent with epidemiological
observations of a negative relationship between SZ and RA reflecting, at least
in part, genetic factors. Results of the month of birth analysis are consistent
with pleiotropic effects of genetic variants dependent on an environmental
context [31].
Pathogenesis of psychiatric comorbidities:
-
Inflammation: pro- and anti-inflammatory cytokines mediate
indoleamine 2,3-dioxygenase activity; this enzyme drives metabolism
of tryptophan and kynurenine in the central nervous system and
degrades serotonin
-
Genetic association: shared pathogenesis at the DNA level or
downstream; single nucleotide polymorphisms that conferred risk is
localized solely to the extended HLA region; allelic variation at
DRB1 pleiotropically modulates risk of rheumatic disease and
psychiatric comorbidities.
Impact of psychiatric disorders on rheumatic diseases
In one study of RA patients, a strong association between depression and anxiety
and the subjective components of the disease activity score (DAS28) was shown
for tender joint count and patient global assessment. After adjusting for age,
gender, disease duration, baseline tender joint count and patient global
assessment respectively, higher levels of depression and anxiety at baseline
were associated with increased tender joint count and patient global assessment
scores at 1-year follow-up. Symptoms of depression and anxiety have implications
for disease activity, as measured by DAS28, primarily due to their influence on
tender joints and patient global assessment [32].
Moreover, research on patient adherence demonstrated a non-significant
association between anxiety and noncompliance. The relationship between
depression and noncompliance, however, was substantial and significant (OR 3.03,
95% CI 1.96–4.89). Compared with nondepressed patients, the odds
are 3 times greater that depressed patients will be noncompliant with medical
treatment recommendations. Evidence of strong covariation of depression and
medical noncompliance suggests the importance of recognizing depression as a
risk factor for poor outcomes among patients who might not be adhering to
medical advice [33]. Moreover, the social
context of individuals with RA affects both their coping strategies and their
psychological responses to the disease, and can impair responses to treatment
through disruption of patient-physician relationships and treatment adherence
[34].
One study in patients with psoriatic arthritis (PsA) revealed that psychosocial
burden of PsA negatively affects health-related quality of life (QoL). Patients
suffered from sleep disorders, fatigue, low-level stress, depression and
mood/behavioral changes, poor body image, and reduced work productivity.
Additionally, each patient responds to pain differently, depending on a variety
of psychological factors including personality structure, cognition, and
attention to pain. PsA is associated with a considerable psychosocial burden and
new assessment tools, specific to PsA, have been developed to help quantify this
burden in patients. Future management algorithms of PsA should incorporate
appropriate assessment and management of psychological and physical concerns of
patients. Furthermore, patients with PsA should be managed by a
multidisciplinary team that works in coordination with the patient and their
family or caregivers [35]. It has been
shown that in patients with autoimmune diseases, when depression coexists, the
quality of life is worse and medical treatment and management is compromised.
Depression-like symptoms, such as fatigue and lack of interest, are also common
in inflammatory rheumatic diseases and are often associated with poor quality of
life [25].
Activity of rheumatic diseases and psychiatric disorders
Mental health comorbidities in rheumatic diseases could interact with disease
processes, including dysregulation of inflammatory responses, prolonged
difficulties with pain and fatigue, and the development of cognitive and
behavioural responses that could exacerbate the physical and psychological
difficulties associated with rheumatic diseases [34].
One study showed that in RA patients the incidence of depression and anxiety was
higher than in patients with osteoarthritis (OA) but they experienced lower
levels of pain, which was more expressed in OA patients. With regard to
autoimmune disorders, these symptoms may reflect the direct effect of cytokines
on the central nervous system. As far as it concerns chronic-degenerative
diseases, anxiety and depression are usually considered
“reactive” to pain, not “constitutive” [36]. Among rheumatic diseases, SLE reveals
the highest frequency of central nervous symptoms. Psychiatric abnormalities of
various severity, including anxiety disorders, depressive symptomatology and
psychosis are present in over 90% of the patients. Reactive depression
in coping with a chronic disease is, however, a psychologically plausible factor
in addition to specific cerebral lesions [37]. A metaanalysis of 48 studies in patients with SSc revealed that
disease-specific symptoms (swollen joints, gastrointestinal and respiratory
symptoms and digital ulcers) and factors related to physical appearance were
associated with negative emotions and development of psychiatric disorders [14]. Another population-based study between
1989 and 2012 aimed to determine whether the incidence of psychiatric disorders
is increased in the 5 years before the diagnosis of some autoimmune diseases
(AD). As early as 5 years before diagnosis, the incidence of depression (IRR
1.54; 95% CI 1.30–1.84) and anxiety disorders (IRR 1.30;
95% CI 1.12–1.51) was elevated in the AD cohort. In addition,
the incidence of BD was elevated beginning 3 years before AD diagnosis (IRR
1.63; 95% CI 1.10–2.40) [20].
Possible interactions of psychiatric disorders and rheumatic diseases
Impact of antirheumatic therapy on psychiatric disorders
Steroids
In animals, stress and corticosteroids can be associated with both reversible
and irreversible changes in the hippocampus. Changes in memory and
hippocampal structure, perhaps in part due to cortisol elevations, are
reported in some patients with mood disorders. Minimal data are available on
the effects of long-term exposure to corticosteroids on the human
hippocampus. In patients with rheumatic diseases receiving long-term
prednisone therapy, greater depressive symptom severity, poorer memory and
smaller hippocampal volumes was noted compared to controls. In this report,
patients and controls were assessed a mean of 4 years after the first
assessment to determine if depressive and manic symptoms and cognition
changed over time. Follow-up MRIs for hippocampal volume analysis were
available in prednisone-treated participants. With the exception of an
increase in depressive symptoms in those receiving prednisone, participants
and controls did not show significant changes in mood or cognition from the
initial assessment. Of interest, one participant discontinued prednisone and
showed improvement in psychiatric symptoms and cognition. Hippocampal
volumes showed inconsistent findings. Although preliminary in nature, the
results suggest that long-term prednisone therapy is associated with initial
changes in mood, memory and hippocampal volume that appear to stabilize over
time. However, in this study the results were not adjusted for disease
activity [38]. In addition, one study
found that steroid use was a potential protective factor for the development
of SZ [23]. Furthermore,
corticosteroid drugs may be effective in alleviating mild psychiatric
symptoms as well [37].
Allopurinol
Since bipolar disorder (BD) seems to be associated with purinergic system
dysfunction, allopurinol might be effective in treating symptoms of mania. A
systematic review and meta-analysis of 5 randomised placebo-controlled
trials (RCTs) analysed the effects of adjunctive allopurinol on BD symptom.
Participants with allopurinol had a significantly greater decrease in mania
symptoms than those with placebo (P=0.007), especially in people
with the most severe forms of mania. Remission rates were significantly
higher among individuals receiving allopurinol, whereas there was no
difference for discontinuation and side-effects [39] . Another double blind,
placebo-controlled study included BD patients during acute mania were
randomly assigned either to a treatment (sodium valproate 15–20
mg/kg+300 mg allopurinol twice a day) or to a control
condition (sodium valproate 15–20 mg/kg+placebo).
Compared to the control group, uric acid levels and symptoms of mania
decreased significantly over time in the treatment group. Probability of
remission after 4 weeks was 23 times higher in the treatment group than in
the control group and lower uric acid levels after 4 weeks were associated
with symptom improvements. Allopurinol using as an augmentation agent to
mood stabilizers or anti-psychotics was tested only for 4 weeks (information
about of side effects of the relative high doses of allopurinol was not
available) [40].
NSAID
Clinical trials with non-steroidal anti-inflammatory drugs (NSAID) in
patients with psychiatric disorders demonstrated positive effects and it has
been proposed to be of clinical use in the treatment of psychiatric
disorders [24]. For example,
Cyclooxygenase- (COX) inhibitors not only reduce the levels of
proinflammatory cytokines, but also affects glutamatergic neurotransmission
and tryptophan/kynurenine metabolism. Several studies have been
performed with celecoxib in SZ; the studies found a therapeutic effect,
mainly in the early stages of the disorder. In addition, a statistically
significant therapeutic effect of celecoxib on depressive symptoms was
detectable in a study with patients with major depression [27]. A meta-analysis appears to support
the use of NSAIDs in acute depression; the effects of celecoxib for which
the best evidence exists to date mainly bias the overall effect. Efficacy
data of non-selective COX inhibitors on depressive symptoms are limited and
out of 6 studies, only a retrospective analysis shows positive results for a
non-selective COX inhibitor. The main problematic factor is that current
evidence rests on trials in acute depression. Because of the dynamic nature
of depression, it is important to explore if NSAIDs and other
anti-inflammatory treatments may have a preventive role in early stages of
depression and for relapse prevention [41]. Furthermore, 5 RCTs (4 unipolar depression studies and one
bipolar depression study) were meta-analyzed. The add-on celecoxib group had
a statistically significant decrease in means of the HADS score at week 4
(pooled difference in means=3.3, 95% CI 1.2–5.3,
p=0.002) and week 6 (pooled difference in means=3.43,
95% CI 1.9–4.9, p<0.0001). The add-on celecoxib
group also showed higher response (OR 6.6, 95% CI 2.5–17,
p<0.0001) and remission rates (OR 6.6, 95% CI
2.7–15.9, p<0.0001) compared with the placebo group [42]. However, results with NSAIDs have
been mixed in human observational studies, with both better and worse
depression outcomes reported. Four small (pooled N=160) randomized
controlled trials suggest that celecoxib (200–400 mg/d) as
co-medication of an antidepressant therapy improves 4–6 week
outcomes in major depressive disorder. The most recent metaanalysis included
26 RCTs suggesting that anti-inflammatory agents reduced depressive symptoms
(SMD -0.55, 95% CI -0.75 to -0.35,
I2=71%) compared with placebo. Higher response
(RR 1.52, 95% CI 1.30 to 1.79, I2=29%)
and remission rates (RR 1.79, 95% CI 1.29 to 2.49,
I2=41%) were seen in the group receiving
anti-inflammatory agents than in those receiving placebo [43]. There are no data, however, to
support the use of celecoxib or other NSAIDs in antidepressant-resistant
depression. There are also concerns about adverse events associated with
NSAID treatment and about pharmacodynamic drug interactions between these
drugs and serotonin reuptake inhibitors [44]. The possible impact of anti-inflammatory treatments on
immune changes in different phases of depression warrants caution for a wide
and preventive use of anti-inflammatory agents in depression-associated
inflammation [41].
DMARDs
Increased concentrations of inflammatory biomarkers predict antidepressant
nonresponse, and inflammatory cytokines can sabotage and circumvent the
mechanisms of action of conventional antidepressants. Therefore, a study was
performed with medically stable outpatients with major depression who were
either on a consistent antidepressant regimen (n=37) or
medication-free (n=23) for 4 weeks or more and who were moderately
resistant to treatment as determined by the Massachusetts General Hospital
Staging method. The patients received 3 infusions of the TNF antagonist
infliximab (5 mg/kg) (n=30) or placebo (n=30) in a
12-week trial. There was no overall difference in the Hamilton Depression
Scale ( HAM-D )scores between treatment groups over time. However, there was
a significant interaction between treatment and biomarker for inflammation.
Increased hs-CRP concentration at baseline was correlated with a better
response to Infliximab (P=0.01). A treatment response
(≥50% reduction in HAM-D score at any point during
treatment) was observed in 62% patients (8 of 13) of
infliximab-treated patients with elevated CRP vs. 33% patients (3 of
9) in the placebo group. In addition, baseline concentrations of TNF and its
soluble receptors were significantly higher in infliximab-treated responders
vs. non-responders (P<0.05), and infliximab-treated responders
exhibited significantly greater decreases in hs-CRP from baseline to week 12
compared with placebo-treated responders (P<0.01). This
proof-of-concept study suggests that TNF antagonism does not have
generalized efficacy in treatment-resistant depression but may improve
depressive symptoms in patients with high baseline inflammatory biomarkers
[45].
Furthermore, another study was performed to investigate the prevalence of
depression in RA patients starting anti-TNF therapy and how mood alters
after exposure to anti-TNF. Patients starting anti-TNF therapy were assessed
for depression using the Hospital Anxiety and Depression Scale (HADS-D).
Change in mood was assessed together with disease activity parameters for 12
months. Patients who remained persistently depressed at 4 months had their
clinical case notes reviewed to determine whether their low mood had been
recognized or treated. Depression was common in this cohort. Depressed
patients had higher DAS28 scores at all time points, and patients with
persistent depression had smaller reductions in DAS28 (P=0.005).
Only 57% (13/23) patients with persistent depression at 4
months had their depression recognized or managed within the rheumatology
clinic. Depression is common but under-recognized in RA patients starting on
anti-TNF therapy. Patients with persistent depression tended to respond less
well to anti-TNF with smaller reductions in DAS28 [46].
A systematic review of the literature regarding the efficacy of
anti-inflammatory drugs in major depressive disorder (MDD), SZ and BD
patients was performed. The results indicated that COX-2 specific inhibitors
showed effectiveness in SZ. Again, anti-TNF-alpha showed effectiveness in
resistant MDD with blood inflammatory abnormalities [47].
In patients with rheumatic diseases, few studies have been published focusing
on psychiatric disorders. One study included 105 RA patients who were
treated with methotrexate, leflunomide, hydroxychloroquine and biologics.
The patients using methotrexate and leflunomide reported lower scores on
suicidal ideation than those using hydroxychloroquine and biologics. Greater
scores for depression, as a comorbidity in RA, increased the rate of
suicidal ideation. Patients taking biologics had the highest rates of
depression, anxiety and suicidal ideation among all patients studied. In
general, it has to be taken into account that there is a bias concerning
disease activity and severity between the medications studied. However,
psychiatric aspects such as depression, anxiety and even suicide ideation
should be addressed in patients with rheumatic diseases [48]. It has also been noted that there
are distinct configurations of conditions conducive to anxiety and
depression in both anti-inflammatory and biologic agent groups. The observed
constellation of dependencies between variables indicates that the choice of
treatment scheme differentiates pain levels. This confirms the assumption
that pain intensity, coping strategies, and resilience depend on the
severity of anxiety and depression [49].
On the other hand, patients with RA and comorbid psychiatric disorders had
poor persistence of MTX and TNF therapies. The results suggest that earlier
discontinuation and low adherence to therapy among patients with RA with
these psychiatric comorbidities may contribute to worse disease outcomes.
Mechanisms by which these comorbidities contribute to lower adherence
deserve further investigation and may lead to targeted interventions to
improve disease outcomes [50].
Furthermore, the potential side effects of biological agents may increase
the anxiety levels of patients and influence not only their desire to use
these therapies but also their adherence to treatment. A study of 1134
patients who were using biologics for at least 3 months with a diagnosis of
a rheumatic disease revealed that general anxiety levels were elevated. The
most common cause for drug-related concerns was the potential side effects
of the drugs (59.5%). Among the potential side effects, cancer risk
was the most common cause for concern (40.1%), followed by the risk
of tuberculosis activation (30.7%). Anxiety levels were higher in
patients who experienced side effects than in other patients and this
difference was statistically significant (P<0.05). Anxiety related
to biological agents may significantly affect the patientsʼ anxiety levels.
Awareness regarding the patientsʼ concerns and expectations related to the
drug is important to ensure drug adherence and concordance to treatment
[51].
Treatment of rheumatic disease and psychiatric comorbidities
-
Steroids
-
greater depressive symptom severity, poorer memory and
smaller hippocampal volumes in patients receiving
long-term prednisone therapy
-
potential protective factor for the development of
schizophrenia
-
may be effective in alleviating mild psychiatric
symptoms
-
NSAR
-
DMARDs
-
anti-TNF-alpha showed important effectiveness in
resistant major depressive disorder with elevated
biomarkers for inflammation
-
patients with persistent depression tended to respond
less well to anti-TNF therapy
-
potential side effects of biological agents may increase
the anxiety levels of patients and influence treatment
adherence
