Abstract
Objective:
Late life depression (LLD) may have a significant vascular component. While this organic basis remains controversial it would explain the refractory nature of LLD. Moreover, depression is a risk factor for venous thrombus embolism (VTE). This paper aims to describe two elderly patients with LLD who developed and were treated for pulmonary embolism (PE).
Methods:
Two cases of elderly patients who developed PE while they were undergoing inpatient treatment for depression are presented. This is discussed using the vascular and the cytokine hypotheses of depression as an explanatory framework.
Results:
Both patients showed significant clinical improvement in their mental state following therapeutic enoxaparin despite no other changes to their management of depression. This observed benefit of enoxaparin can be explained by the vascular hypothesis of LLD, and possibly the cytokine hypothesis of major depression.
Conclusion:
Enoxaparin may be a novel adjunct to the treatment of depression in elderly patients. The possible benefit of enoxaparin would require further study to exclude a coincidence in these clinical cases.
Late life depression (LLD) affects approximately 2–5% of elderly patients and is associated with cerebrovascular comorbidities and cerebral small vessel disease. 1 The vascular depression hypothesis suggests that cerebrovascular disease may precipitate, predispose and perpetuate LLD and may account for up to 50% of LLD.1,2 The hypothesis remains controversial, 3 despite the number of clinical studies that support the hypothesis. 4
The relationship between depression and vascular pathology is not confined to neuropathology. In their systematic review, Van der Kooy et al. found that clinically diagnosed depression in elderly patients is a strong risk factor for the development of cardiovascular disease. 5 The INTERHEART study showed a relationship between depression and myocardial infarction. 6 Population studies have found that depression in all ages increases the risk of venous thrombus embolism (VTE), even when other risk factors are controlled.7,8 There are behavioural and biological factors that may explain this relationship, 9 and antidepressant usage has been shown to increase the risk of VTE.10,11
Feldinger previously reported the case of an elderly patient who developed VTE and showed improvement of cognition and depression following commencement of therapeutic enoxaparin; no other cases have been reported. 12 Here, we report two further cases and propose a possible mechanism.
Case presentations
Case 1
JD is an 80-year-old lady who was treated for depression following a brief hypomanic episode. Premorbidly, she was an active and independent lady. Her psychiatric history was significant for depression, with two prior hospital admissions, the most recent 20 years ago. Her past medical history was significant for asthma and deep vein thrombosis (DVT). She had never received electroconvulsive therapy (ECT), and had remained well in recent years without antidepressant medication. Her family history included one daughter with postnatal depression.
Two months prior to admission, JD was prescribed prednisolone (up to 50 mg daily) for an acute exacerbation of asthma. She became agitated and confused as the dose was reduced over a week, and she began wandering the house at night. She then became markedly depressed in mood, with psychomotor retardation. She was commenced on fluvoxamine at home, and quetiapine was added when she arrived in hospital.
On admission, mental state examination revealed a very low mood, with passive suicidal ideation. Affect was labile and thought content was dominated by negativistic ruminations approaching delusional intensity.
Olanzapine was commenced after admission and slowly titrated upwards, and prednisone was slowly weaned. Quetiapine was ceased. Sodium valproate was commenced and well-tolerated. Despite early improvements, JD’s progress plateaued by the 3rd week of admission.
JD developed an unprovoked bilateral pulmonary embolism (PE) on day 20 of her admission, and was immediately commenced on therapeutic enoxaparin. She was transferred to a medical ward for observation. She remained haemodynamically stable and was transferred back to the mental health unit.
Four days after treatment with enoxaparin commenced, JD’s mental state examination showed a significant improvement. Her mood was greatly improved, and she was laughing and joking with the staff. No further medication changes had been made.
Case 2
RM is a 69-year-old gentleman who was treated for depression with psychotic features. He was initially brought to hospital by ambulance following self-harm (deep laceration to neck) with high intent to suicide. Collateral history from his sons later revealed this was his third serious suicide attempt. His past history was significant for depression. He had a significant family history of psychiatric illness: one son has depression, and his daughter had schizophrenia (she died aged 20 by suicide). Prior to admission he was not compliant with psychotropic medications. This suicide attempt was preceded by a progressive decline during the preceding months, and RM later reported symptoms of worsening anhedonia, anorexia and social avoidance leading to isolation.
On admission, RM was almost mute, with flat affect and low mood, and clinical features of psychomotor retardation. He refused oral fluid or food intake, and voiced ongoing suicidal thoughts. He denied positive psychotic symptoms, although he later divulged beliefs with melancholic themes of delusional intensity.
Olanzapine was commenced and RM underwent two sessions of ECT titration. RM developed an unprovoked saddle PE on day 5 of admission prior to his third ECT session. He was commenced on therapeutic enoxaparin and spent 3 days in the intensive care unit (ICU). There remained ongoing concerns of a risk of the embolus dislodging during the ECT procedure and ECT was delayed by a full week.
Remarkably, RM’s mental state improved by day 2 of ICU admission. He began smiling and speaking in three-word sentences. He was transferred to a respiratory ward and remained haemodynamically stable while continuing to show improvement in his mental state. RM showed some interest in food and he continued to exhibit an improvement in mental state despite the delay in treatment.
Discussion
The two cases presented here are clinically very different. It is the differences that suggest the possibility that the psychological benefit of enoxaparin may not be coincidental, and their commonality suggests a cause. The timing of improvement in mental state was within the first 3 days of therapeutic enoxaparin. Both patients had no changes in antidepressant medication for over 3 weeks prior to their PE, which would coincide with the efficacy time frame of antidepressant medication. While RM had received two ECT sessions, these were titration sessions and were probably subtherapeutic. Indeed, the rate of response could not be explained by psychotropic medication alone.
Enoxaparin primarily binds to antithrombin III, thereby interrupting thrombin generation by inhibiting factor Xa and thrombin. It is indicated in the initial treatment of VTE, prophylaxis of VTE in medical patients and treatment for myocardial infarction and unstable angina. The LIVE-ENOX study showed the safety and efficacy of enoxaparin in pregnant women with thrombophilia and recurrent pregnancy loss. 13 Animal studies have found that enoxaparin may also be neuroprotective in acute cerebral ischaemia and traumatic brain injury,14,15 and has a vasodilatory effect on human tissue. 16
These vascular effects, as well as the vascular nature of LLD may hint at a possible vascular mechanism that can explain the observed effects described in this paper. We propose that microemboli accumulate gradually over the years, in line with the vascular hypothesis; depression and cognitive decline may be global brain effects rather than a results of known neurochemical processes of depression. Therapeutic doses of enoxaparin would be sufficient to dissolve the microemboli and dilate cerebral arteries, thereby improving blood flow and global brain function.
However, enoxaparin has previously been observed to have immune-modulating effects by inhibiting the pro-inflammatory cytokine TNF-α.17,18 The cytokine hypothesis of major depression therefore offers an alternate mechanism by which enoxaparin could improve depression. The cytokine hypothesis proposes a role of elevated levels of pro-inflammatory cytokines in the development of depression. 19 Depressed patients have significantly increased levels of TNF- α and IL-6 20 and pro-inflammatory cytokines alter serotonin and glutamate. 21 Therefore, inhibition of pro-inflammatory cytokines by enoxaparin could result in an increase in the level of serotonin, thereby improving mood via the serotonin pathway. Indeed, similar observations have been reported with celecoxib – a cyclooxygenase-2 inhibitor. 22
The observations described in this paper suggest the hypothesis that enoxaparin is a safe and effective biological adjunct to the treatment of depression. A well-designed observational study is required to verify the findings described in this paper and thereby support the proposed hypothesis. Once verified, a clinical randomised control trial will be required to validate the clinical effectiveness of therapeutic enoxaparin as a biological adjunct.
Conclusion
The two cases presented in this paper suggest that therapeutic doses of enoxaparin in the setting of PE may have concomitant benefits in the treatment of depression. The vascular hypothesis, and possibly the cytokine hypothesis, offers a mechanism that could explain the apparent beneficial effect of therapeutic enoxaparin in the treatment of LLD.
Footnotes
Acknowledgements
The authors wish to thank JD and RM and their families.
Disclosure
The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
