Shared Pathways, Distinct Contexts: Depression Across Organ Failure, Neurological Diseases, and Reproductive Transitions

CATEGORY 1 CME

Premiere Date: April 20, 2026 

Expiration Date: October 20, 2027

This activity offers CE credits for: 

1. Physicians (CME) 

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To inform readers of common presentations and challenges related to depression in those with a medical illness.

LEARNING OBJECTIVES

1. Recognize and differentiate depressive syndromes in patients with systemic medical illnesses, including transplant recipients, patients with neurological disorders, and those who undergo reproductive transitions, while distinguishing depressive symptoms from overlapping medical or neurological symptoms.

2. Apply evidence-based screening and treatment strategies for depression in medically complex populations, including consideration of pharmacologic interactions, organ dysfunction, and the role of psychotherapy and multidisciplinary care.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC and Psychiatric Times. Physicians’ Education Resource, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource, LLC. No commercial support was received.

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Depressive disorders in those with systemic medical illness can be conceptualized through a biopsychosocial lens.¹ Several medical conditions have a biopsychosocial overlay that culminates in a depressive syndrome. There are high rates of depression in medical conditions ranging from cancer to diabetes mellitus to coronary artery disease.^2-4 An in-depth exploration of all common and chronic medical conditions is beyond the scope of this article. Instead, we aim to illustrate common presentations and challenges related to depression in those with medical illness; for example, distinguishing the neurovegetative symptoms of depression from the symptoms associated with the illness itself.^5,6

The prevalence of depression has been generally shown to be higher among individuals on chronic hemodialysis than in patients preemptive for dialysis (29.9% vs 18.5% per a 2024 systematic review and meta-analysis) and among those on hemodialysis compared with peritoneal dialysis (30.6% vs 20.4%).⁷

Depression in hemodialysis is treated pharmacologically following the typical algorithm of depression management—selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, or bupropion, with dose adjustments and considerations of whether a drug is dialyzable. Psychotherapy has also been found to be helpful.^8,9

Patients with metabolic dysfunction–associated steatotic liver disease (MASLD) experience significantly higher rates of depression than those who do not have MASLD. Additionally, those with depression have a significantly higher risk of developing MASLD than patients without depression, indicating a bidirectional link.¹⁰

Transplantation

Screening and evaluation for depression is an important aspect of the psychosocial evaluation prior to transplantation. Those with a history of depression and those who actively screen positive for depressive symptoms are referred by social work to psychiatry for further assessment. Identifying and treating depressive disorders before transplantation is recommended to prevent posttransplant depression. Depressive symptomatology is an important part of the assessment for psychological stability, as included in validated tools such as the Stanford Integrated Psychosocial Assessment
for Transplantation.

Posttransplant prevalence of depressive symptoms is estimated at 14% to 75% for heart transplant recipients, 5% to 75% for kidney transplant recipients, 13.7% to 67% for liver transplant recipients, and 22% to 30% for lung transplant recipients.¹¹

In addition to major depressive disorder (MDD; estimated between 25.5% and 41% prevalence), adjustment disorders are common after transplantation (10.7%). Demoralization was noted in 32.6% of heart transplant recipients. The following pretransplant factors are associated with a higher risk of posttransplant depression: alcohol use disorder, a history of depressive or mood disorder, acute rejection, longer time on ventilation for lung transplant recipients, the severity of heart failure, physical status, and limited physical activity.¹¹

Patients are very often prescribed corticosteroids post transplant, which are associated with mood disorders. Immunosuppressants such as tacrolimus are associated with a host of neuropsychiatric symptoms. Depression has been linked with worse outcomes in solid organ transplant recipients.¹² Posttransplant depressive disorders have been associated with graft dysfunction and increased health care utilization, and depressive symptoms have been associated with poorer medication adherence and quality of life. A meta-analysis of 27 studies found that depressive symptoms and depressive disorders increase the relative risk of mortality among solid organ transplant recipients by 65%.

The Academy of Consultation-Liaison Psychiatry (ACLP) Best Practice Guideline for the evaluation and treatment of depression in solid organ transplant recipients makes several recommendations: For recipients over the age of 18 years, the recommended screening for depression is once in the first 6 months post transplantation and a second time before 1 year post transplantation, and then yearly afterward, using the Patient Health Questionnaire (PHQ) -2, -8, or -9, the Hospital Anxiety and Depression Scale, or the Patient-Reported Outcomes Measurement Information System-57 and -29. Treatment for depression in organ transplant recipients should be initiated and guided by clinical assessment and should not be based on screening measures alone. Treatment should be offered by clinicians with expertise in transplant mental health or in general psychiatry. Treatment of a preexisting depressive disorder before surgery has been recognized in the guidelines as the leading intervention to prevent depression after transplant.¹¹

Antidepressants such as sertraline, citalopram, escitalopram, and mirtazapine are generally considered acceptable first-line agents for the treatment of depression. Among other agents, it is important to consider drug-drug interactions and adverse effects. Fluvoxamine is a CYP3A4 inhibitor that may increase the serum concentrations of tacrolimus, a commonly used immunosuppressant, and it also inhibits CYP1A2 and CYP2C19. Fluoxetine has a long half-life and, like paroxetine, has many drug-drug interactions. Fluoxetine and paroxetine inhibit C2D6 to a substantial extent. Paroxetine additionally has a short half-life, no active metabolites, and has anticholinergic properties, often rendering it a suboptimal choice. Escitalopram has a favorable drug-drug interaction profile and is well tolerated. Sertraline has been evaluated as being safe in several populations, including patients with post myocardial infarction, and mirtazapine is helpful in transplant patients who also struggle with insomnia and poor appetite. An additional consideration in patients being evaluated for transplants is thrombocytopenia, which is common in liver disease and may limit the use of SSRIs and SNRIs, as they inhibit platelet aggregation. Bupropion is considered a safer choice in those with thrombocytopenia. The least preferred agents are monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), and fluvoxamine.¹¹

In terms of psychotherapy, cognitive behavioral therapy (CBT) and interpersonal psychotherapy have been found to be highly effective in treating depression in different populations. A few considerations when treating depression with pharmacological agents in this population:

1. Is the agent being used toxic to the organ in question?
2. Is the agent metabolized by the organ in question?
3. Are any dose adjustments needed, given the presence of cirrhosis, which can alter metabolism, or a reduction in estimated glomerular filtration rate that can alter the clearance of the drug?

A transplant is a life-altering event, and transplant patients have a wide variety of psychosocial needs at various points in their journey and experience depression at significant rates. It is important to screen transplant recipients for depression and to adequately address depression to optimize posttransplant survival and quality of life.

Neurological Disorders

Antidepressants, including SSRIs and SNRIs, can worsen motor symptoms in Parkinson disease (PD) and interact with antiparkinsonian drugs such as selegiline and rasagiline, increasing the risk of serotonin syndrome.

Antiepileptic drugs such as carbamazepine, phenytoin, and barbiturates can lower the levels of antidepressant drugs, potentially resulting in treatment failure. In contrast, certain antidepressants (fluoxetine and fluvoxamine) can increase blood levels of these medications, increasing the risk of toxicity. Antidepressants such as bupropion and TCAs can lower the seizure threshold and are to be used with caution in patients with epilepsy. Antidepressants with strong anticholinergic effects, such as TCAs, can lower the efficacy of anticholinesterase inhibitors, such as donepezil (Aricept), in Alzheimer disease (AD).

Depression is among the most common comorbid conditions across major neurological diseases and is often underrecognized and undertreated due to overlapping symptoms and diagnostic challenges in patients with cognitive or motor deficits.¹³ Untreated depression can exacerbate neurological symptoms, reduce treatment adherence, erode quality of life, and interfere with self-management, leading to accelerated disease progression and contributing to elevated suicide rates in patients with neurological disorders.¹⁴ Depression rates are significantly elevated in many neurological conditions, with estimated prevalence rates of approximately 20% to 50%; the highest rates are in refractory epilepsy, Huntington disease (HD), multiple sclerosis, PD, traumatic brain injury, and stroke.¹⁵

The etiology of depression in neurological diseases is likely multifactorial, including altered signaling of neurotransmitters, changes in brain structure, inflammation, disrupted neurotrophic factors, and psychosocial agents.¹³ In some neurological disorders, such as AD, epilepsy, and stroke, evidence indicates a bidirectional relationship where depression can be a risk factor for certain neurological disorders, such as major neurocognitive disorder/dementia and stroke onset.¹⁶ Both dementia and depression are diseases with a high prevalence and with a remarkable overlap in their epidemiological data.^17,18 The presence of late depressive symptoms could be a prodromal factor of dementia.^19,20 On the other hand, individuals with depression have an increased risk of being diagnosed with dementia.^21,22 In a recent study by Canton-Habas et al, data showed that participants with a diagnosis of depression had between a 13.6- and 15.6-times higher prevalence of dementia than participants without depression.²³

Similarly, in PD, a large-scale prospective study demonstrated that depression prevalence increases from 10 years before PD diagnosis and is a marker of cortical and subcortical volume loss. Depression before PD diagnosis signals a worse prognosis in terms of dementia and mortality. This has clinical implications in stratifying patients with poorer cognitive and prognostic trajectories in PD.²⁴

Depression is usually diagnosed and evaluated based on the presence of affective symptoms only. In contrast, other symptoms, especially cognitive symptoms, are often overlooked and may be critical for accurate diagnosis, treatment, functional recovery, and the patient’s quality of life.^13,25 It is important to distinguish depression in neurological conditions from other depression mimics, including apathy, demoralization, pseudodementia, hypoactive delirium, and pathological affect, which are described in the Table. Treating depression in neurological disorders must include assessment, a clinical interview of the patient and/or caregiver, and a thorough assessment of cognitive status, physical functioning, and somatic symptoms related to the neurological condition.

Standardized screening scales, such as the PHQ-9, that are used for depression screening may be less effective. A major limitation of scales is that they are self-reported and subject to the patient’s insight and subjective judgment, which is often absent in the context of diseases associated with dementia.¹³

The Screening for Cognitive Impairment in Psychiatry (SCIP) and the Cognitive Complaints in Bipolar Disorder Rating Assessment tools are 2 new cognitive assessment screening tools recently validated in patients with MDD. The SCIP requires less than 20 minutes and can assess verbal learning, working memory, verbal fluency, delayed memory, and processing speed.²⁶

In summary, managing depression in neurological diseases requires a multidisciplinary approach. An increased awareness and evaluation of lesser-known symptoms of depression, such as cognitive decline, is of significant importance. Treatment includes psychotropic medications, CBT, and somatic interventions (including electroconvulsive therapy in treatment-refractory cases), but very often the evidence-based efficacy is extremely limited. SSRIs and SNRIs remain the first line of treatment for depression secondary to neurologic conditions.13 However, the use of SSRIs has been associated with the presence of apathy and emotional blunting, and in conditions with dopamine and noradrenaline deficiency, such as PD, the use of SNRIs may reduce the severity or residual apathetic symptoms.^27,28

In HD, findings from studies show a higher efficacy for TCAs, tetracyclic antidepressants, and SNRIs than SSRIs.²⁹

Although there is limited evidence supporting the generalized use of antidepressants in dementia,³⁰ data from recent placebo-controlled studies have shown the efficacy of escitalopram and sertraline for improving depression in AD. Mirtazapine, an antagonist of serotonin receptors and peripheral adrenergic receptors, used at doses up to 45 mg/day, has also shown efficacy in treating symptoms of depression in AD based on data from network meta-analysis.^31-33 Electroconvulsive therapy and transcranial magnetic stimulation can be used when pharmacological management has been ineffective.

Reproductive Transitions

Premenstrual dysphoric disorder (PMDD) involves a range of severe mood symptoms with a temporal association to the menstrual cycle. There is a 1.8% to 5.8% 12-month prevalence in menstruating people, though estimates of clinically significant premenstrual symptoms are higher.³⁴ To understand how neurobiological factors influence conditions such as PMDD, a general comprehension of the reproductive cycle is vital. The menstrual cycle lasts an average of 28 days and is divided into 2 phases: the follicular phase, followed by the luteal phase.³⁵

The cycle begins with the follicular phase, which corresponds with the first day of menses and the release of follicle-stimulating hormone, which aids in ovarian follicle growth. As a follicle matures, it produces estrogen. Ovulation occurs midway through at day 14, corresponding to a surge in luteinizing hormone that causes the follicle to release an egg from the ovary. The luteal phase begins as ovulation occurs and corresponds to an increase in progesterone. Progesterone levels decline prior to the onset of menses. If no pregnancy occurs during the cycle, progesterone levels decline. If pregnancy occurs, progesterone and estrogen levels remain elevated to support the embryo and only decline upon delivery of the placenta.³⁶

A diagnosis of PMDD requires 5 of 11 specific symptoms, which must be present in the last week before menses and improve with the onset of menses.³⁷ Symptoms occur in the luteal phase of the menstrual cycle, when progesterone levels decrease and estrogen levels remain low. Symptoms otherwise are minimal or absent during the follicular phase.³⁸

PMDD symptoms span both affective and physical/behavioral categories, and symptoms must be associated with most menstrual cycles within the past year and cause a significant impairment in function. To confirm the diagnosis, symptoms must be tracked prospectively for at least 2 menstrual cycles to meet diagnostic criteria. Affective symptoms include lability, irritability, depressed mood, and anxiety, while the behavioral/cognitive symptoms include anhedonia, concentration impairment, low energy, changes in sleep or appetite, a sense of being overwhelmed, and physical symptoms.³⁸ The etiology of PMDD is thought to be driven by genetic susceptibility; progesterone and allopregnanolone levels; estrogen, serotonin, and brain-derived neurotrophic factor levels; structural and functional brain differences; and involvement of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axis.³⁷ This interplay coalesces into one overarching theme in the pathogenesis of PMDD: abnormal sensitivity to the normal fluctuations in hormones during the menstrual cycle.

Neuroactive metabolites of progesterone are thought to be essential contributors. Most evidence implicates allopregnanolone, which interacts with GABAA receptors in the brain and modulates the affective symptoms of PMDD. The withdrawal of these neurosteroids, either during the menstrual cycle or in the postpartum period, influences the development of affective symptoms, rather than absolute levels of the hormones.^36,37 Hormonal shifts in the postpartum period have a similar impact on mood and led to the suspicion that PMDD may be a risk factor for postpartum depression (PPD). A leading hypothesis behind PPD is related to the rapid shifts in steroid hormones in the postpartum period.^36,39 Developing evidence suggests a strong relationship between the 2: Patients diagnosed with PMDD are twice as likely to develop PPD.³⁶

Understanding the connection between these major biological systems guides the treatment approach for PMDD. SSRI treatment is the gold standard, as it increases progesterone metabolism to allopregnanolone and normalizes the neurosteroid tolerance observed during the luteal phase in PMDD.^38,40 The mechanism by which SSRIs treat PMDD is hypothesized to be distinct from the mechanism by which they are thought to treat other depressive and anxiety disorders, as the effect on symptoms is often rapid and achieved with low doses.³⁸

There are 2 primary methodologies for dosing SSRIs for PMDD. One is luteal phase dosing, where menstruating patients take the medications on days 14 to 28 of the menstrual cycle when progesterone levels begin to decline.³⁸ Luteal phase dosing of SSRIs has been shown to improve symptoms that persist into the follicular phase. Alternatively, luteal phase dosing of fluoxetine can also be efficacious when given as a single dose of 90 mg 14 days before menses, corresponding to ovulation, then again 7 days before menses, about midway through the luteal phase.³⁸

Another method is symptom-triggered or symptom-onset dosing.³⁸ Medications are started only with the onset of premenstrual symptoms. Data from recent studies suggest this strategy to be more effective than placebo in trials of sertraline for severe premenstrual syndrome and escitalopram for PMDD.³⁸ Medications are often prescribed in combination with therapy, with CBT being one of the most well-studied modalities with efficacy in treating PMDD, particularly mindfulness-based CBT.^38,40 Additional options often carried out in collaboration with colleagues in gynecology include oral contraceptives, gonadotropin-releasing hormone agonists, and surgery.³⁸ Complementary and alternative methods include supplements such as chasteberry extract, calcium, and vitamin B6; exercise has also shown some benefit for symptoms.³⁸

Although not medically ill states, the menstrual cycle and postpartum period represent a period of significant hormonal fluctuations and demonstrate how, in susceptible individuals, depressive symptoms can develop. PMDD and PPD highlight how medically complex hormonal shifts can contribute to depressive symptoms.

Concluding Thoughts

Medical illnesses can impact the way in which depression presents, and cultivating an awareness of how depression can manifest is an essential skill in psychiatry. Myriad medical complexities exist, from organ transplantation to neurological disorders to the interplay of hormones with mood and behaviors, which have distinct influences on the development of depression. By enhancing one’s conceptualization of depression, one can more fully assess, recognize, and treat depressive symptoms in patients with medical illness.

Dr Kalra is a psychiatrist in the Department of Behavioral Health at the Palo Alto Medical Foundation Group in California.

Dr Mutalik is an assistant professor of psychiatry at the Icahn School of Medicine at Mount Sinai, in New York, New York.

Dr Katchmar is a consultation liaison psychiatry fellow at the Hospital of the University of Pennsylvania in Philadelphia.

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