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Psychiatry Online

  • March 01, 2024 | VOL. 75, NO. 3 CURRENT ISSUE pp.203-304
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A Literature Review of Studies of Depression and Treatment Outcomes Among U.S. College Students Since 1990

  • Elissa J. Miller M.D., M.P.H.
  • Henry Chung M.D.

Search for more papers by this author

According to the fall 2007 American College Health Association-National College Health Assessment ( 1 ), a national survey of approximately 20,500 college students on 39 campuses, 43.2% of the students reported "feeling so depressed it was difficult to function" at least once in the past 12 months. More than 3,200 university students reported being diagnosed as having depression, with 39.2% of those students diagnosed in the past 12 months, 24.2% currently in therapy for depression, and 35.8% taking antidepressant medication. Among the students surveyed, 10.3% admitted "seriously considering attempting suicide" within the past 12 months and 1.9% actually attempted suicide during that period.

Although the above data may seem surprising to some, it is not to most mental health clinicians and administrators at U.S. colleges. According to the 2008 National Survey of Counseling Center Directors, 95% of respondents believe that there has been a trend in recent years of an increase in the number of students with serious psychological problems. In 2008 an estimated 26% of counseling center clients were taking psychiatric medication, up from 20% in 2003, 17% in 2000, and 9% in 1994 ( 2 ). And although the rate of suicide among college students may have decreased in recent decades ( 3 ), suicide remains the third leading cause of death among adolescents and young adults ( 4 ).

Many college administrators have begun to appreciate the effect that a student's depression can have on overall functioning in the college community. Depression has been linked to academic difficulties as well as interpersonal problems at school, with more severe depression correlated with higher levels of impairment ( 5 ). The treatment of depression among college students has been associated with a protective effect on these students' grade point averages ( 6 ). In an effort to diagnose and treat early and effectively, and thus decrease the excess morbidity and risk of suicide associated with depression, some U.S. colleges have even begun to screen students for depression in the primary care setting ( 7 ).

There are unique challenges of providing treatment to college students. These challenges include significant academic pressure in semester-based cycles, extensive semester breaks that result in discontinuities of care, and heavy reliance on community supports that can be inconsistent. Given the prevalence and impact of depression on college campuses and the varying services offered by university mental health centers throughout the United States, there is a significant need to evaluate successful models of treatment and their related outcomes.

The databases PsycINFO, MEDLINE, and CINAHL were searched for studies related to depression among U.S. college students and treatment outcome by using the following terms: "depression," "college or university or graduate or junior college or community college students," "colleges," "community colleges," "treatment and prevention," "empirical study," and "peer reviewed journal." Initially, no limitation was placed on years included in the search. Eighteen relevant publications were read and analyzed closely for method and content, with particular focus on location and inclusion criteria of study participants. Studies were eliminated if participants were students at colleges outside of the United States, if the studies did not have specific depression criteria for inclusion, or if the students included were at risk of depression but did not meet criteria for having depression. Nine remaining articles were reviewed further, and it was decided that the five studies published before 1990 had decreased relevance and would be excluded from this review in light of the growing availability of selective serotonin reuptake inhibitor medications since 1990, which substantially changed the treatment of depression among college students. In addition, the demographic characteristics of U.S. college students may have changed since the early 1990s, with many college counseling center directors noting a trend in recent years of an increase in students with serious psychological problems ( 2 ). Only four articles ( 8 , 9 , 10 , 11 ) remained for this review of depression and treatment outcomes of U.S. college students.

In 2007 Kelly and colleagues ( 8 ) conducted a nonexperimental study that recruited from introductory psychology classes university students with depression who were not currently in treatment, offering both financial compensation and class credit for research involvement. Sixty college students (66% Caucasian, 57% female) with major depression were followed for nine weeks without any treatment to assess for sudden gains (that is, precipitous improvements in depressive symptomatology), remission of depressive symptoms, and reversal of improvements. The authors found that 60% of the college students with major depression experienced sudden gains over the nine weeks of not receiving treatment. However, before the end of the nine-week observation period, more than half of these sudden gains reversed. At the end of the period of not receiving treatment, depression was in remission for 20% of the students. The authors concluded that sudden gains may be part of the natural course of depression for some college students, irrespective of treatment, and that self-evaluation processes may play an important role in recovery.

In 2000 Lara and colleagues ( 9 ) conducted a nonexperimental study in which undergraduate students taking psychology classes who had a recent-onset major depressive episode were paid or received course credit for their research participation. Eighty-four students (51% Caucasian, 86% female) were followed for 26 weeks to assess whether various psychosocial factors predicted the short-term course of major depression. The authors found that within the 26-week period of no treatment, 68% of the college students who were initially depressed recovered. Among those who recovered, 21% relapsed by the end of the 26-week period into another major depressive episode. Lara and colleagues concluded that college students with depression may sometimes spontaneously recover and relapse and that harsh discipline in childhood was significantly associated with higher mean levels of depression at follow-up and relapse but not with recovery.

In 2006 Geisner and colleagues ( 10 ) conducted a four-week randomized controlled trial of depression treatment and recruited undergraduates with depression who were enrolled in psychology courses to participate for course credit. The study enrolled 177 students with depression (49% Caucasian and 48% Asian, 70% female) who were randomly assigned either to an intervention group that received personalized mailed feedback or to a control group. The authors found that depressive symptoms improved for both the intervention and control groups, but in the intervention condition there was a significantly greater improvement of depressive symptoms, as measured by the DSM-IV-Based Depression Scale. There was no significant difference between the intervention and control groups on symptoms measured by the Beck Depression Inventory (BDI). Geisner and colleagues concluded that an intervention using personalized mailed feedback may be useful for reducing depressive symptoms among college students.

In 1993 Pace and Dixon ( 11 ) conducted a four- to seven-week randomized controlled trial to assess the treatment effectiveness of individual cognitive therapy for college students with depressive symptoms. Participating undergraduate students earned course credit for their research involvement. Seventy-four students (100% Caucasian, 81% female) who met strict criteria for study inclusion were randomly assigned to either a group that received individual cognitive therapy or a control condition where participants did not receive treatment and were put on a waiting list for cognitive therapy. Pace and Dixon found that 74% of participants in the cognitive therapy group (versus 33% in control group) were classified as nondepressed with BDI scores of less than 10 after four to seven weeks of treatment. At the one-month follow-up, 81% of participants in the cognitive therapy group (versus 64% of control group) were classified as nondepressed. Outcomes at both time points were statistically significant in favor of cognitive therapy. The authors concluded that brief individual cognitive therapy may effectively reduce mild to moderate depressive symptoms as well as depressive self-schemata among college students.

The current body of literature on depression and treatment outcomes among U.S. college students is sparse, and for the four studies we found, varying inclusion and exclusion criteria, assessment methods, and lengths of treatment make the interpretation of results difficult. Whereas Kelly and colleagues ( 8 ) and Lara and colleagues ( 9 ) used the Structured Clinical Interview for DSM-IV to diagnose participants with major depressive disorder, Geisner and colleagues ( 10 ) and Pace and Dixon ( 11 ) used self-report scales to measure depressive symptoms for study inclusion and Pace and Dixon excluded students with severe levels of depressive symptoms. All four studies recruited students who were not seeking treatment and who were offered course credit for participating, a reward that might have influenced the degree of improvement in outcomes. There was no consistent standard used across studies to define a student with depression, even when using the same assessment tool. In terms of length of treatment, only two of the four reviewed studies followed students for more than nine weeks. The length of time over which students are assessed is especially critical for the college population, where time is defined by a semester calendar, moods are often influenced by exam schedules, and treatments are adjusted to accommodate upcoming vacations ( 12 ). Today's college mental health services tend to employ short-term models of care (eight to 16 sessions), with referral to outside clinicians if longer-term treatment is necessary ( 13 ). Given these dynamics, future research in college mental health will need to establish quality standards for ongoing monitoring and follow-up of students' treatment outcomes.

Unfortunately, the results from these four studies may not be fully applicable to college students today or in the future, particularly in light of the changing demographic characteristics of those attending universities as well as the rapidly evolving role of pharmacology in the treatment of depression. Only two of the four studies reviewed offered any active treatment for depression, and none of the studies included any form of pharmacological treatment. Consistent with current medical literature and best practices, many treatment-seeking college students diagnosed as having depression currently receive psychotherapy and psychopharmacological treatment ( 1 ). Because major depression can be a chronic recurring condition, future research needs to evaluate the effectiveness of the various treatment modalities used to treat college students with depression. This is particularly important in light of the recent addition of a black-box warning for the use of antidepressant medications among young adults aged 18 to 24 years, which recommends the close monitoring of patients taking antidepressant medication for clinical worsening, suicidality, or unusual changes in behavior.

Conclusions

In light of the high prevalence of depression among college students today and the risks and sequelae this illness poses if not diagnosed and treated early and effectively, it is imperative that research funding be increased for both naturalistic and intervention studies of depression and treatment outcomes in the college health setting. First, research documenting depression and treatment outcomes in this cohort should be identified in order to evaluate the adequacy of current care. Second, research should be directed to assessing specific short-term or semester-based interventions for students with depression. Models that explore the effectiveness of integration with primary care, care management, medication, and short-term psychotherapy are all important targets for future study. By conducting such research, effective treatment models and benchmarks of treatment outcome in the college population can be developed and integrated into college mental health practice.

Acknowledgments and disclosures

The authors thank Michael Klein, Ph.D., for his assistance in the development of this brief report.

Dr. Chung has served on advisory boards for Takeda Pharmaceuticals and Lundbeck Pharmaceuticals and has served as a speaker for Pfizer and Jazz Pharmaceuticals. Dr. Miller reports no competing interests.

At the time of this report, Dr. Miller was a Public Psychiatry Fellow at New York State Psychiatric Institute and Columbia University, New York City. Dr. Chung is associate vice-president of student health at New York University Student Heath Center, New York City. Send correspondence to Dr. Miller at the New York State Psychiatric Institute, Columbia University, 1051 Riverside Dr., Box 111, New York, NY 10032 (e-mail: [email protected] ).

1. American College Health Association-National College Health Assessment: Reference Group Report, Fall 2007. Baltimore, American College Health Association, 2008. Available at www.acha-ncha.org/reports_ACHA-NCHAoriginal.html Google Scholar

2. Gallagher R: National Survey of Counseling Center Directors, Alexandria, Va, International Association of Counseling Services, 2008. Available at www.iacsinc.org Google Scholar

3. Schwartz A: Four eras of study of college student suicide in the United States: 1920–2004. Journal of American College Health 54:353–366, 2006 Google Scholar

4. National Center for Injury Prevention and Control: Web-based Injury Statistics Query and Reporting System (WISQARS). Atlanta, Ga, Centers for Disease Control and Prevention, 2005. Available at www.cdc.gov/injury/wisqars/index.html Google Scholar

5. Heiligenstein E, Guenther G, Hsu K, et al: Depression and academic impairment in college students. Journal of American College Health 45:59–64, 1996 Google Scholar

6. Hysenbegasi A, Hass S, Rowland C: The impact of depression on the academic productivity of university students. Journal of Mental Health Policy and Economics 8:145–151, 2005 Google Scholar

7. Chung H, Klein M: Improving identification and treatment of depression in college health. Student Health Spectrum, June 2007, pp 13–19 Google Scholar

8. Kelly M, Roberts J, Bottonari K: Non-treatment related sudden gains in depression: the role of self-evaluation. Behaviour Research and Therapy 45:737–747, 2007 Google Scholar

9. Lara ME, Klein DN, Kasch KL: Psychosocial predictors of the short-term course and outcome of major depression: a longitudinal study of a nonclinical sample with recent-onset episodes. Journal of Abnormal Psychology 109:644–650, 2000 Google Scholar

10. Geisner I, Neighbors C, Larimer M: A randomized clinical trial of a brief, mailed intervention for symptoms of depression. Journal of Consulting and Clinical Psychology 74:393–399, 2006 Google Scholar

11. Pace T, Dixon D: Changes in depressive self-schemata and depressive symptoms following cognitive therapy. Journal of Counseling Psychology 40:288–294, 1993 Google Scholar

12. Lee C: Evidenced-based treatment of depression in the college population. Journal of College Student Psychotherapy 20:23–31, 2005 Google Scholar

13. Stone G, McMichael J: Thinking about mental health policy in university and college counseling centers. Journal of College Student Psychotherapy 10:3–28, 1996 Google Scholar

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literature review on depression pdf

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  • Systematic Review
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  • Published: 20 July 2022

The serotonin theory of depression: a systematic umbrella review of the evidence

  • Joanna Moncrieff 1 , 2 ,
  • Ruth E. Cooper 3 ,
  • Tom Stockmann 4 ,
  • Simone Amendola 5 ,
  • Michael P. Hengartner 6 &
  • Mark A. Horowitz 1 , 2  

Molecular Psychiatry volume  28 ,  pages 3243–3256 ( 2023 ) Cite this article

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The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT 1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n  = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use ( n  = 1869). Two meta-analyses of overlapping studies examining the 5-HT 1A receptor (largest n  = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n  = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers ( n  = 566), but weak evidence of an effect in those with a family history of depression ( n  = 75). Another systematic review ( n  = 342) and a sample of ten subsequent studies ( n  = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study ( n  = 115,257) and one collaborative meta-analysis ( n  = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

Introduction

The idea that depression is the result of abnormalities in brain chemicals, particularly serotonin (5-hydroxytryptamine or 5-HT), has been influential for decades, and provides an important justification for the use of antidepressants. A link between lowered serotonin and depression was first suggested in the 1960s [ 1 ], and widely publicised from the 1990s with the advent of the Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants [ 2 , 3 , 4 ]. Although it has been questioned more recently [ 5 , 6 ], the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support [ 7 , 8 ], leading researchers endorsing it [ 9 , 10 , 11 ], and much empirical research based on it [ 11 , 12 , 13 , 14 ]. Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance’ [ 15 , 16 ]. Many general practitioners also subscribe to this view [ 17 ] and popular websites commonly cite the theory [ 18 ].

It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general [ 19 , 20 ].

Despite the fact that the serotonin theory of depression has been so influential, no comprehensive review has yet synthesised the relevant evidence. We conducted an ‘umbrella’ review of the principal areas of relevant research, following the model of a similar review examining prospective biomarkers of major depressive disorder [ 21 ]. We sought to establish whether the current evidence supports a role for serotonin in the aetiology of depression, and specifically whether depression is associated with indications of lowered serotonin concentrations or activity.

Search strategy and selection criteria

The present umbrella review was reported in accordance with the 2009 PRISMA statement [ 22 ]. The protocol was registered with PROSPERO in December 2020 (registration number CRD42020207203) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=207203 ). This was subsequently updated to reflect our decision to modify the quality rating system for some studies to more appropriately appraise their quality, and to include a modified GRADE to assess the overall certainty of the findings in each category of the umbrella review.

In order to cover the different areas and to manage the large volume of research that has been conducted on the serotonin system, we conducted an ‘umbrella’ review. Umbrella reviews survey existing systematic reviews and meta-analyses relevant to a research question and represent one of the highest levels of evidence synthesis available [ 23 ]. Although they are traditionally restricted to systematic reviews and meta-analyses, we aimed to identify the best evidence available. Therefore, we also included some large studies that combined data from individual studies but did not employ conventional systematic review methods, and one large genetic study. The latter used nationwide databases to capture more individuals than entire meta-analyses, so is likely to provide even more reliable evidence than syntheses of individual studies.

We first conducted a scoping review to identify areas of research consistently held to provide support for the serotonin hypothesis of depression. Six areas were identified, addressing the following questions: (1) Serotonin and the serotonin metabolite 5-HIAA–whether there are lower levels of serotonin and 5-HIAA in body fluids in depression; (2) Receptors - whether serotonin receptor levels are altered in people with depression; (3) The serotonin transporter (SERT) - whether there are higher levels of the serotonin transporter in people with depression (which would lower synaptic levels of serotonin); (4) Depletion studies - whether tryptophan depletion (which lowers available serotonin) can induce depression; (5) SERT gene – whether there are higher levels of the serotonin transporter gene in people with depression; (6) Whether there is an interaction between the SERT gene and stress in depression.

We searched for systematic reviews, meta-analyses, and large database studies in these six areas in PubMed, EMBASE and PsycINFO using the Healthcare Databases Advanced Search tool provided by Health Education England and NICE (National Institute for Health and Care Excellence). Searches were conducted until December 2020.

We used the following terms in all searches: (depress* OR affective OR mood) AND (systematic OR meta-analysis), and limited searches to title and abstract, since not doing so produced numerous irrelevant hits. In addition, we used terms specific to each area of research (full details are provided in Table  S1 , Supplement). We also searched citations and consulted with experts.

Inclusion criteria were designed to identify the best available evidence in each research area and consisted of:

Research synthesis including systematic reviews, meta-analysis, umbrella reviews, individual patient meta-analysis and large dataset analysis.

Studies that involve people with depressive disorders or, for experimental studies (tryptophan depletion), those in which mood symptoms are measured as an outcome.

Studies of experimental procedures (tryptophan depletion) involving a sham or control condition.

Studies published in full in peer reviewed literature.

Where more than five systematic reviews or large analyses exist, the most recent five are included.

Exclusion criteria consisted of:

Animal studies.

Studies exclusively concerned with depression in physical conditions (e.g. post stroke or Parkinson’s disease) or exclusively focusing on specific subtypes of depression such as postpartum depression, depression in children, or depression in bipolar disorder.

No language or date restrictions were applied. In areas in which no systematic review or meta-analysis had been done within the last 10 years, we also selected the ten most recent studies at the time of searching (December 2020) for illustration of more recent findings. We performed this search using the same search string for this domain, without restricting it to systematic reviews and meta-analyses.

Data analysis

Each member of the team was allocated one to three domains of serotonin research to search and screen for eligible studies using abstract and full text review. In case of uncertainty, the entire team discussed eligibility to reach consensus.

For included studies, data were extracted by two reviewers working independently, and disagreement was resolved by consensus. Authors of papers were contacted for clarification when data was missing or unclear.

We extracted summary effects, confidence intervals and measures of statistical significance where these were reported, and, where relevant, we extracted data on heterogeneity. For summary effects in the non-genetic studies, preference was given to the extraction and reporting of effect sizes. Mean differences were converted to effect sizes where appropriate data were available.

We did not perform a meta-analysis of the individual meta-analyses in each area because they included overlapping studies [ 24 ]. All extracted data is presented in Table  1 . Sensitivity analyses were reported where they had substantial bearing on interpretation of findings.

The quality rating of systematic reviews and meta-analyses was assessed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) [ 25 ]. For two studies that did not employ conventional systematic review methods [ 26 , 27 ] we used a modified version of the AMSTAR-2 (see Table  S3 ). For the genetic association study based on a large database analysis we used the STREGA assessment (STrengthening the REporting of Genetic Association Studies) (Table  S4 ) [ 28 ]. Each study was rated independently by at least two authors. We report ratings of individual items on the relevant measure, and the percentage of items that were adequately addressed by each study (Table  1 , with further detail in Tables  S3 and S4 ).

Alongside quality ratings, two team members (JM, MAH) rated the certainty of the results of each study using a modified version of the GRADE guidelines [ 29 ]. Following the approach of Kennis et al. [ 21 ], we devised six criteria relevant to the included studies: whether a unified analysis was conducted on original data; whether confounding by antidepressant use was adequately addressed; whether outcomes were pre-specified; whether results were consistent or heterogeneity was adequately addressed if present; whether there was a likelihood of publication bias; and sample size. The importance of confounding by effects of current or past antidepressant use has been highlighted in several studies [ 30 , 31 ]. The results of each study were scored 1 or 0 according to whether they fulfilled each criteria, and based on these ratings an overall judgement was made about the certainty of evidence across studies in each of the six areas of research examined. The certainty of each study was based on an algorithm that prioritised sample size and uniform analysis using original data (explained more fully in the supplementary material), following suggestions that these are the key aspects of reliability [ 27 , 32 ]. An assessment of the overall certainty of each domain of research examining the role of serotonin was determined by consensus of at least two authors and a direction of effect indicated.

Search results and quality rating

Searching identified 361 publications across the 6 different areas of research, among which seventeen studies fulfilled inclusion criteria (see Fig.  1 and Table  S1 for details of the selection process). Included studies, their characteristics and results are shown in Table  1 . As no systematic review or meta-analysis had been performed within the last 10 years on serotonin depletion, we also identified the 10 latest studies for illustration of more recent research findings (Table  2 ).

figure 1

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagramme.

Quality ratings are summarised in Table  1 and reported in detail in Tables  S2 – S3 . The majority (11/17) of systematic reviews and meta-analyses satisfied less than 50% of criteria. Only 31% adequately assessed risk of bias in individual studies (a further 44% partially assessed this), and only 50% adequately accounted for risk of bias when interpreting the results of the review. One collaborative meta-analysis of genetic studies was considered to be of high quality due to the inclusion of several measures to ensure consistency and reliability [ 27 ]. The large genetic analysis of the effect of SERT polymorphisms on depression, satisfied 88% of the STREGA quality criteria [ 32 ].

Serotonin and 5-HIAA

Serotonin can be measured in blood, plasma, urine and CSF, but it is rapidly metabolised to 5-hydroxyindoleacetic acid (5-HIAA). CSF is thought to be the ideal resource for the study of biomarkers of putative brain diseases, since it is in contact with brain interstitial fluid [ 33 ]. However, collecting CSF samples is invasive and carries some risk, hence large-scale studies are scarce.

Three studies fulfilled inclusion criteria (Table  1 ). One meta-analysis of three large observational cohort studies of post-menopausal women, revealed lower levels of plasma 5-HT in women with depression, which did not, however, reach statistical significance of p  < 0.05 after adjusting for multiple comparisons. Sensitivity analyses revealed that antidepressants were strongly associated with lower serotonin levels independently of depression.

Two meta-analyses of a total of 19 studies of 5-HIAA in CSF (seven studies were included in both) found no evidence of an association between 5-HIAA concentrations and depression.

Fourteen different serotonin receptors have been identified, with most research on depression focusing on the 5-HT 1A receptor [ 11 , 34 ]. Since the functions of other 5-HT receptors and their relationship to depression have not been well characterised, we restricted our analysis to data on 5-HT 1A receptors [ 11 , 34 ]. 5-HT 1A receptors, known as auto-receptors, inhibit the release of serotonin pre-synaptically [ 35 ], therefore, if depression is the result of reduced serotonin activity caused by abnormalities in the 5-HT 1A receptor, people with depression would be expected to show increased activity of 5-HT 1A receptors compared to those without [ 36 ].

Two meta-analyses satisfied inclusion criteria, involving five of the same studies [ 37 , 38 ] (see Table  1 ). The majority of results across the two analyses suggested either no difference in 5-HT 1A receptors between people with depression and controls, or a lower level of these inhibitory receptors, which would imply higher concentrations or activity of serotonin in people with depression. Both meta-analyses were based on studies that predominantly involved patients who were taking or had recently taken (within 1–3 weeks of scanning) antidepressants or other types of psychiatric medication, and both sets of authors commented on the possible influence of prior or current medication on findings. In addition, one analysis was of very low quality [ 37 ], including not reporting on the numbers involved in each analysis and using one-sided p-values, and one was strongly influenced by three studies and publication bias was present [ 38 ].

The serotonin transporter (SERT)

The serotonin transporter protein (SERT) transports serotonin out of the synapse, thereby lowering the availability of serotonin in the synapse [ 39 , 40 ]. Animals with an inactivated gene for SERT have higher levels of extra-cellular serotonin in the brain than normal [ 41 , 42 , 43 ] and SSRIs are thought to work by inhibiting the action of SERT, and thus increasing levels of serotonin in the synaptic cleft [ 44 ]. Although changes in SERT may be a marker for other abnormalities, if depression is caused by low serotonin availability or activity, and if SERT is the origin of that deficit, then the amount or activity of SERT would be expected to be higher in people with depression compared to those without [ 40 ]. SERT binding potential is an index of the concentration of the serotonin transporter protein and SERT concentrations can also be measured post-mortem.

Three overlapping meta-analyses based on a total of 40 individual studies fulfilled inclusion criteria (See Table  1 ) [ 37 , 39 , 45 ]. Overall, the data indicated possible reductions in SERT binding in some brain areas, although areas in which effects were detected were not consistent across the reviews. In addition, effects of antidepressants and other medication cannot be ruled out, since most included studies mainly or exclusively involved people who had a history of taking antidepressants or other psychiatric medications. Only one meta-analysis tested effects of antidepressants, and although results were not influenced by the percentage of drug-naïve patients in each study, numbers were small so it is unlikely that medication-related effects would have been reliably detected [ 45 ]. All three reviews cited evidence from animal studies that antidepressant treatment reduces SERT [ 46 , 47 , 48 ]. None of the analyses corrected for multiple testing, and one review was of very low quality [ 37 ]. If the results do represent a positive finding that is independent of medication, they would suggest that depression is associated with higher concentrations or activity of serotonin.

Depletion studies

Tryptophan depletion using dietary means or chemicals, such as parachlorophenylalanine (PCPA), is thought to reduce serotonin levels. Since PCPA is potentially toxic, reversible tryptophan depletion using an amino acid drink that lacks tryptophan is the most commonly used method and is thought to affect serotonin within 5–7 h of ingestion. Questions remain, however, about whether either method reliably reduces brain serotonin, and about other effects including changes in brain nitrous oxide, cerebrovascular changes, reduced BDNF and amino acid imbalances that may be produced by the manipulations and might explain observed effects independent of possible changes in serotonin activity [ 49 ].

One meta-analysis and one systematic review fulfilled inclusion criteria (see Table  1 ). Data from studies involving volunteers mostly showed no effect, including a meta-analysis of parallel group studies [ 50 ]. In a small meta-analysis of within-subject studies involving 75 people with a positive family history, a minor effect was found, with people given the active depletion showing a larger decrease in mood than those who had a sham procedure [ 50 ]. Across both reviews, studies involving people diagnosed with depression showed slightly greater mood reduction following tryptophan depletion than sham treatment overall, but most participants had taken or were taking antidepressants and participant numbers were small [ 50 , 51 ].

Since these research syntheses were conducted more than 10 years ago, we searched for a systematic sample of ten recently published studies (Table  2 ). Eight studies conducted with healthy volunteers showed no effects of tryptophan depletion on mood, including the only two parallel group studies. One study presented effects in people with and without a family history of depression, and no differences were apparent in either group [ 52 ]. Two cross-over studies involving people with depression and current or recent use of antidepressants showed no convincing effects of a depletion drink [ 53 , 54 ], although one study is reported as positive mainly due to finding an improvement in mood in the group given the sham drink [ 54 ].

SERT gene and gene-stress interactions

A possible link between depression and the repeat length polymorphism in the promoter region of the SERT gene (5-HTTLPR), specifically the presence of the short repeats version, which causes lower SERT mRNA expression, has been proposed [ 55 ]. Interestingly, lower levels of SERT would produce higher levels of synaptic serotonin. However, more recently, this hypothesis has been superseded by a focus on the interaction effect between this polymorphism, depression and stress, with the idea that the short version of the polymorphism may only give rise to depression in the presence of stressful life events [ 55 , 56 ]. Unlike other areas of serotonin research, numerous systematic reviews and meta-analyses of genetic studies have been conducted, and most recently a very large analysis based on a sample from two genetic databanks. Details of the five most recent studies that have addressed the association between the SERT gene and depression, and the interaction effect are detailed in Table  1 .

Although some earlier meta-analyses of case-control studies showed a statistically significant association between the 5-HTTLPR and depression in some ethnic groups [ 57 , 58 ], two recent large, high quality studies did not find an association between the SERT gene polymorphism and depression [ 27 , 32 ]. These two studies consist of  by far the largest and most comprehensive study to date [ 32 ] and a high-quality meta-analysis that involved a consistent re-analysis of primary data across all conducted studies, including previously unpublished data, and other comprehensive quality checks [ 27 , 59 ] (see Table  1 ).

Similarly, early studies based on tens of thousands of participants suggested a statistically significant interaction between the SERT gene, forms of stress or maltreatment and depression [ 60 , 61 , 62 ], with a small odds ratio in the only study that reported this (1.18, 95% CI 1.09 to 1.28) [ 62 ]. However, the two recent large, high-quality studies did not find an interaction between the SERT gene and stress in depression (Border et al [ 32 ] and Culverhouse et al.) [ 27 ] (see Table  1 ).

Overall results

Table  3 presents the modified GRADE ratings for each study and the overall rating of the strength of evidence in each area. Areas of research that provided moderate or high certainty of evidence such as the studies of plasma serotonin and metabolites and the genetic and gene-stress interaction studies all showed no association between markers of serotonin activity and depression. Some other areas suggested findings consistent with increased serotonin activity, but evidence was of very low certainty, mainly due to small sample sizes and possible residual confounding by current or past antidepressant use. One area - the tryptophan depletion studies - showed very low certainty evidence of lowered serotonin activity or availability in a subgroup of volunteers with a family history of depression. This evidence was considered very low certainty as it derived from a subgroup of within-subject studies, numbers were small, and there was no information on medication use, which may have influenced results. Subsequent research has not confirmed an effect with numerous negative studies in volunteers.

Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers. High quality, well-powered genetic studies effectively exclude an association between genotypes related to the serotonin system and depression, including a proposed interaction with stress. Weak evidence from some studies of serotonin 5-HT 1A receptors and levels of SERT points towards a possible association between increased serotonin activity and depression. However, these results are likely to be influenced by prior use of antidepressants and its effects on the serotonin system [ 30 , 31 ]. The effects of tryptophan depletion in some cross-over studies involving people with depression may also be mediated by antidepressants, although these are not consistently found [ 63 ].

The chemical imbalance theory of depression is still put forward by professionals [ 17 ], and the serotonin theory, in particular, has formed the basis of a considerable research effort over the last few decades [ 14 ]. The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities [ 15 , 16 ], and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood [ 64 , 65 , 66 ]. The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs [ 67 , 68 ].

As with all research synthesis, the findings of this umbrella review are dependent on the quality of the included studies, and susceptible to their limitations. Most of the included studies were rated as low quality on the AMSTAR-2, but the GRADE approach suggested some findings were reasonably robust. Most of the non-genetic studies did not reliably exclude the potential effects of previous antidepressant use and were based on relatively small numbers of participants. The genetic studies, in particular, illustrate the importance of methodological rigour and sample size. Whereas some earlier, lower quality, mostly smaller studies produced marginally positive findings, these were not confirmed in better-conducted, larger and more recent studies [ 27 , 32 ]. The identification of depression and assessment of confounders and interaction effects were limited by the data available in the original studies on which the included reviews and meta-analyses were based. Common methods such as the categorisation of continuous measures and application of linear models to non-linear data may have led to over-estimation or under-estimation of effects [ 69 , 70 ], including the interaction between stress and the SERT gene. The latest systematic review of tryptophan depletion studies was conducted in 2007, and there has been considerable research produced since then. Hence, we provided a snapshot of the most recent evidence at the time of writing, but this area requires an up to date, comprehensive data synthesis. However, the recent studies were consistent with the earlier meta-analysis with little evidence for an effect of tryptophan depletion on mood.

Although umbrella reviews typically restrict themselves to systematic reviews and meta-analyses, we aimed to provide the most comprehensive possible overview. Therefore, we chose to include meta-analyses that did not involve a systematic review and a large genetic association study on the premise that these studies contribute important data on the question of whether the serotonin hypothesis of depression is supported. As a result, the AMSTAR-2 quality rating scale, designed to evaluate the quality of conventional systematic reviews, was not easily applicable to all studies and had to be modified or replaced in some cases.

One study in this review found that antidepressant use was associated with a reduction of plasma serotonin [ 26 ], and it is possible that the evidence for reductions in SERT density and 5-HT 1A receptors in some of the included imaging study reviews may reflect compensatory adaptations to serotonin-lowering effects of prior antidepressant use. Authors of one meta-analysis also highlighted evidence of 5-HIAA levels being reduced after long-term antidepressant treatment [ 71 ]. These findings suggest that in the long-term antidepressants might produce compensatory changes [ 72 ] that are opposite to their acute effects [ 73 , 74 ]. Lowered serotonin availability has also been demonstrated in animal studies following prolonged antidepressant administration [ 75 ]. Further research is required to clarify the effects of different drugs on neurochemical systems, including the serotonin system, especially during and after long-term use, as well as the physical and psychological consequences of such effects.

This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers [ 21 ]. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.

Data availability

All extracted data is available in the paper and supplementary materials. Further information about the decision-making for each rating for categories of the AMSTAR-2 and STREGA are available on request.

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JM conceived the idea for the study. JM, MAH, MPH, TS and SA designed the study. JM, MAH, MPH, TS, and SA screened articles and abstracted data. JM drafted the first version of the manuscript. JM, MAH, MPH, TS, SA, and REC contributed to the manuscript’s revision and interpretation of findings. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 28 , 3243–3256 (2023). https://doi.org/10.1038/s41380-022-01661-0

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Neuropsychological research provides a useful framework to study emotional problems, such as depression, and their correlates. This paper reviews several prominent neuropsychological theories. Functional neuroanatomical systems of emotion and depression are reviewed, including those that describe cerebral asymmetries in emotional processing. Following the review, a model that is composed of three neuroanatomical divisions (left frontal, right frontal, and right posterior) and corresponding neuropsychological emotional sequelae within each quadrant is presented. It is proposed that dysfunction in any of these quadrants could lead to symptomatology consistent with a diagnosis of depression. The proposed model combines theories of arousal, lateralization, and functional cerebral space and lends itself to scientific methods of investigation. Accordingly, research, prevention, and treatment programs in accordance with the proposed model may promote an improved understanding of the neuropsychological mechanisms involved in depression.

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Shenal, B.V., Harrison, D.W. & Demaree, H.A. The Neuropsychology of Depression: A Literature Review and Preliminary Model. Neuropsychol Rev 13 , 33–42 (2003). https://doi.org/10.1023/A:1022300622902

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Recognizing Depression in the Elderly: Practical Guidance and Challenges for Clinical Management

Maria devita.

1 Department of General Psychology (DPG), University of Padua, Padua, Italy

2 Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy

Rossella De Salvo

Adele ravelli, marina de rui, alessandra coin, giuseppe sergi, daniela mapelli.

Depression is one of the most common mood disorders in the late-life population and is associated with poor quality of life and increased morbidity, disability and mortality. Nevertheless, in older adults, it often remains undetected and untreated. This narrative review aims at giving an overview on the main definitions, clinical manifestations, risk and protective factors for depression in the elderly, and at discussing the main reasons for its under/misdiagnosis, such as cognitive decline and their overlapping symptomatology. A practical approach for the global and multidisciplinary care of the older adult with depression, derived from cross-checking evidence emerging from the literature with everyday clinical experience, is thus provided, as a short and flexible “pocket” guide to orient clinicians in recognizing, diagnosing and treating depression in the elderly.

Introduction

Depression is one of the most common mood disorders in the late-life population. 1 , 2 The prevalence of depressive disorder in the over 60 years old population is about 5.7%. 3 However, it increases with age, to reach the peak of 27% in over-85 individuals. 1 Interestingly, the prevalence still increases and reaches the 49% in those living in communities or nursing homes, 4 , 5 regardless of the severity or the definition of depression considered. 1

Late-life depression (LLD) can be distinguished according to the age at which the first depression occurred. Early-onset depression (EOD) identifies the persistence or recurrence in old age of a depression previously diagnosed throughout adulthood, while late-onset depression (LOD) represents a depressive disorder developed de novo in old age. 6

DSM 5 identifies a cluster of depressive symptoms, namely depressed mood, loss of interest and pleasure, weight loss or gain, fatigue, insomnia or hypersomnia, psychomotor agitation or retardation, decreased concentration, thoughts of death and/or suicide and worthlessness. 3

However, LLD is characterized by an atypical cluster of symptoms, ie somatic symptoms which are predominant compared to mood symptoms, so it is important to be aware of this particular clinical presentation in order to not underestimate LLD.

Moreover, the complex spectrum of Late-Life Depression (LLD) goes beyond the main diagnostic entities of unipolar depressive disorders, such as Major Depressive Disorder (MDD) and persistent depressive disorder. 7 Relevant depressive symptoms which do not fulfill the criteria for a diagnosis of depression have nevertheless a significant clinical relevance, because of their association with poorer quality of life and increased disability; however, they are often undetected and untreated, despite a very small chance of spontaneous remission. 8

Depressive symptoms produce clinically significant distress and impairment in daily life, notching social, familiar, and occupational areas of functioning. Depression is entangled in a bidirectional relationship with somatic morbidity finally resulting in an increase in patients’ burden of disability and frailty and augmenting mortality. 9 In fact, besides being a risk factor and a predictor of poor prognosis for many conditions, like diabetes, cancer, cardiovascular diseases, dementia, 10–12 depression can be precipitated and perpetuated by chronic medical conditions typical of the aging process. A longitudinal study of 3214 healthy elderly individuals proved that Mild Cognitive Impairment (MCI), as well as smoking and mobility, vision, and subjective memory impairments, can significantly increase the risk of depression. 13

Thus, the diagnosis of depression is challenging in elderly people, since it often presents with multifaceted and more somatic symptoms compared to adults, 14 thus resembling a “real” medical organic disease. 5

Also, treatment is demanding, because of the complexity of older patients, who more frequently have a pharmacological-resistant depression and require a multidimensional and, possibly, a multi-professional equipe taking charge.

The objective of this review is, on the one hand, to explain the strong impact of geriatric depression on individual and caregivers’ quality of life and the difficulties in recognizing and prescribing the adequate treatment and, on the other hand, to propose a practical approach for the global and multi-disciplinary care of the older adult with depression, from diagnosis up to the definition of a customized treatment. In order to do so, a short and flexible “pocket” guide is here proposed as a tool to orient clinicians in recognizing, diagnosing and treating depression in the elderly. To the best of our knowledge, there is no tool currently available, such as the here proposed pocket guide, thought to be flexible and easily adaptable to the most disparate clinical contexts.

Reviewing the Literature on Geriatric Depression: Definitions, Risk and Protective Factors, Symptomatology and Clinical Variants

Geriatric depression syndrome: characterization and symptomatology.

While the depression severity appears to remain stable across the lifespan, what really differentiates depression in middle and old age concerns qualitative differences in the clinical presentation of the symptomatology ( Table 1 ).

Depression Symptoms in Younger and Older Adults: Typical and Atypical Presentation

Abbreviations : *DSM, Diagnostic and Statistical Manual of Mental disorders; **GI, gastrointestinal.

As an example, considering depressed mood (sadness or dysphoria) and loss of interest (anhedonia), which are the two core symptoms of Major Depressive Disorder (MDD) according to the DSM 5, they can be manifested differently in older adults compared younger people, 15 as well as inappropriate guilt or feelings of worthlessness. 16 Notably, regarding the first of these two core symptoms (ie depressed mood), feelings of dysphoria or sadness are frequently absent in older adults, 7 underlying a specific variant of geriatric depression indicated as “depression without sadness”, 17 characterized by lack of interest, sleep difficulties, lack of hope, loss of appetite and thoughts of death.

On the contrary, symptoms like lack of vigor and withdrawal, which are referred to the second core symptom of MDD, are usually more pronounced. In fact, “loss of interest” is usually pronounced, since older adults tend to be more apathetic. 18 Suicidal thoughts are frequent in LLD, together with state of anxiety, especially in the morning. 19

What characterizes even more LLD is a shift towards somatic symptoms, 18 which become prominent and vary in their manifestations compared to early onset depression, although the criteria symptoms remain the same. For example, while increased appetite and overeating may frequently occur in younger individuals, loss of appetite and weight are more common in late life. 20 Similarly, considering that sleep duration declines with age, decreased sleep is more common in LLD compared to hypersomnia, which is more typically experienced by younger depressed adults. 18 Fatigue is expressed both as physical tiring and lack of energy rather than a mental symptom, while the “poor concentration” symptom could be manifested more as a broader cognitive impairment where memory loss is related to executive dysfunction. 21 In general, older people manifest more vague and gastrointestinal somatic complaints, together with hypochondriasis. 22 Lastly, psychomotor retardation is more common in LLD than agitation, leading to disturbances in speech, facial expression, fine motor behavior, and gross locomotor activity, which exceed the general slowdown observed in normal aging. 23

It is therefore clear that one of the main challenges in recognizing the diagnostic features of geriatric depression is the overlap of its typical symptoms with those of other comorbid physical or neurologic conditions and, in general, with the typical signs of frailty (ie, weight loss, psychomotor slowing and exhaustion).

In fact, the somatic symptoms that in younger adults are indicative of depression, in the elderly may be correlated with aging and may not be indicative of a specific pathology, as well as could be due to other comorbid conditions. Thus, while including somatic symptoms in geriatric screening for depression regardless of their etiology (inclusive approach) may lead to false positives, 24 it remains true that they cannot be completely excluded from the diagnostic framework (as the exclusive approach, instead, proposes), as aging and its associated conditions do not necessarily justify all these aspects. An alternative is represented by the aetiological approach, in which somatic symptoms are considered only if they are not primarily due to another medical condition. 25 In general, a good clinical practice is to ask people about their mood when they refer to non-specific physical complaints, as to assess the presence of mood problems that older adults tend not to autonomously express, as previously stated.

Geriatric Depression Syndromes

Because of its peculiar features and complexity, different specific variants of geriatric depression have been proposed to better frame its presentations.

Among these, the “depletion syndrome”, 26 characterized by lack of interest, sleep difficulties, lack of hope, loss of appetite and thoughts of death, described the common condition of “depression without sadness” seen in older adults.

Another condition is referred to as “reversible dementia”. In some cases, in fact, older patients suffering from a severe depression development with marked cognitive impairment can induce the clinicians to misdiagnose dementia. 27 However, in these patients, the cognitive symptomatology recedes with the remission of depression, even if a part of them subsequently develops a proper dementia. 28 The label of “pseudodementia” this condition was addressed as, is no longer used, because of the complex relationship between depression and dementia, which represents an interaction between pathological processes, with more than one illness masquerading as another. 29

In fact, the complex entanglement involving aging-related processes, network dysfunction and depressive symptoms is also supported by the fact that two distinct syndromes regarding LOD can be recognized, ie the “depression-executive dysfunction syndrome” (DED) and vascular depression. DED 30 develops in patients whose fronto-striatal pathways are affected by aging-related or pathological changes. It is marked by psychomotor retardation, loss of interest, suspiciousness, lack of insight and pronounced disability, but rather mild vegetative symptoms and less prominent depressive ideation. 31 Moreover, individuals affected by this syndrome have impaired performance in tests of executive functioning (namely verbal fluency, response inhibition, problem solving, cognitive flexibility, working memory and ideomotor planning). 32 Vascular depression, instead, is characterized by psychomotor slowing, lack of initiative and apathy, and it is typically observed in patients with a medical history of hypertension and cognitive impairment. 31 The “vascular depression” hypothesis postulates that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive disorders, 31 disrupting networks supporting affective and cognitive functions. 32

Risk and Protective Factors

The identification of factors that can increase or protect from the risk of developing depression in the elderly population is crucial in order to promote prevention strategies, but also for the best comprehensive approach to this disease. The literature has shown that suffering from a chronic disorder 4 , 33–35 or cognitive impairment, 36 having a weak social, emotional and supportive network, 5 , 37 living isolated, taking care of relatives with chronic disease, 38 losing a partner, 39 can facilitate the rising of depressive symptoms. Furthermore, gender differences, well known in younger patients, persists also into late life, so being a woman can represent a risk factor. 40 On the other hand, having a high level of self-esteem, 41 resilience 42 and sense of control, 41 keeping a healthy lifestyle 43 and having a medium/high level of cognitive reserve 44 represent protective factors for the rising of depression in elderly age. Table 2 provides a detailed overview of the main risk and protective factors involved in geriatric depression.

Risk and Protective Factors for Depression in Elderly

Recognizing Geriatric Depression in the Elderly: A Current Challenge

Depression in older adults is often under- or misdiagnosed and thus undertreated or inappropriately treated. Reasons for underdiagnosis are several and include psychosocial factors too. The first issue concerns the prejudice that depression is a normal phase of aging, because of the medical and situational conditions typical of older age, such as the limitations imposed by functional disability, health concerns and psychological stressors as decreasing social contacts, transitions in key social roles (ie, retirement) and grief. 15 Although, mood deflection is certainly understandable, it does not imply that it should be neglected, nor that it is not treatable, especially when it is a source of suffering and impairs functioning. Another barrier for depression recognition involves stigmatization. In fact, some individuals are reluctant to accept a diagnosis of depression, and often both patients and clinicians may hope to find a “medical illness” in order to avoid the stigma of a psychiatric diagnosis. 20 Moreover, older adults are less likely to express mood problems, like dysphoria or worthlessness, and may describe their symptoms in a more “somatic” way. 7 In general, older adults often find physical illness to be more acceptable than psychiatric illness. 45 At the same time, physicians may lack screening for depression because of more urgent physical problems or because they wrongly attribute depressive symptoms to comorbid medical illness. 46

In addition to underdiagnosis, another factor that contributes to undertreatment is misdiagnosis. As previously stated ( Table 1 ), in the elderly depression has an atypical presentation, including persistent complaints of pain, headache, fatigue, apathy, agitation, insomnia, weight loss, low attention and other nonspecific symptoms which can overlap with or be confused with other physical illnesses and dementia. This can lead clinicians to pursue an expensive medical workup, when they may not be able to recognize these problems as being part of a depressive episode. At the same time, older adults may relate their symptoms to a medical condition, thus not seeking the proper help. 18 Thus, it is necessary to gain insight on variability in the presentation of specific depressive symptoms across the lifespan.

Confounding Factors: Cognitive Impairment and Depression in Older Adults

Another specific challenge in the accurate diagnosis of depression concerns its entanglement with cognitive impairment and dementia. In fact, there is a substantial overlapping in the clinical presentation of late-life depression and early-stage dementia: a subjective perception of memory loss, as well as psychomotor retardation and a lack of motivation in answering at cognitive tests are typically observed in depressed older adults, and can be interpreted as signs of dementia. 47 Moreover, in older adults, depression is commonly accompanied by cognitive deficits, which are present in 20 to 50% of cases. 48 , 49 On the other hand, depressive symptoms are a common neuropsychiatric symptom of Alzheimer’s Disease (AD). 50 Still, given the prevalence of both syndromes in the older population, they can also independently co-occur, and the two diagnoses are not mutually exclusive. 36

Geriatric depression is characterized by cognitive deficits involving executive functions, such as problem solving, planning, decision-making and inhibition, along with selective and sustained attention and working memory impairment. 51 Other deficits, involving some aspects of episodic memory and visuospatial functions, may be secondary to executive dysfunction. 28 These symptoms remain significant even after the remission of the depressive symptomatology. 52 In a 10-year longitudinal study, Ly et al 53 have shown that depressed older adults perform worse than compared healthy controls in cognitive tasks, maybe for the neurotoxic effects of depression and reduced cognitive reserve.

The relationship between late-life depression and cognitive decline is even more complex, considering that, besides mimicking each other, they also can coexist and be mutually a risk factor.

On the one hand, in fact, older adults with dementia can develop pure depressive symptoms. Clinical depression in these cases can be either reactive to the diagnosis or a relapse of a previously diagnosed depression. 54 Olin et al proposed diagnostic criteria for “depression of Alzheimer’s disease”, including the presence of at least three significant depressive symptoms during the same two-week period that represents a significant perturbation from previous functioning, when all the criteria of AD are fulfilled. 55

On the other hand, Ly et al 53 found that late-onset depression, but not EOD, was associated with a more rapid cognitive decline over time. These findings suggest that EOD, whose symptoms are persistent or recurrent in old age, is a vulnerability factor that alters cognitive abilities even in healthy aging, representing a risk factor for dementia. 21 On the contrary, LOD could be a real harbinger of dementia. In particular, highly educated people are more likely to show depressive symptoms as initial presentation of dementia, probably because cognitive reserve may delay the onset of cognitive, but not depressive, symptomatology. 56

Reviewing the Literature on Therapeutic Approaches to Depression in the Elderly

The effective management of geriatric depression builds upon different strategies, involving both pharmacological and non-pharmacological options that have to be considered based on the patient’s characteristics and psychosocial environment, in order to shape a tailored and comprehensive intervention. In fact, the most effective approach is the biopsychosocial one, combining pharmacotherapy, psychotherapy and an array of lifestyle and social environment’s personalized modifications. These therapies and good practices have shown to be effective, resulting in improved quality of life, enhanced functional capacity, possible improvement in medical health status, increased longevity, and lower health care costs. 14

Pharmacological Treatment of Depression in Older Adults

Late-life depression compared with that of younger patients shows a lower response rate to antidepressants, nonetheless several treatment options exist.

When prescribing drugs, including psychotropic drugs, to older adults’ attention should be paid to pharmacokinetic and pharmacodynamic changes associated with aging. In fact, drug distribution varies, due to the increase in body fat that leads to an increasing distribution volume and elimination of half-life for lipophilic drugs. Renal filtration rate decrease enhances the problem of drug elimination. In addition, hepatic metabolism, besides being affected by aging, is also influenced by other concomitant drugs that induce or inhibit cytochrome P-450 metabolic enzymes.

In the choice of antidepressant treatment, the patient’s previous response to treatment should be considered, as well as his/her other comorbidities and medications, in order to minimize the risk of side effects and drug–drug interactions. In addition, somatic symptoms associated with depression like anxiety, psychotic symptoms, insomnia/hypersomnia, hyperphagia/poor nutrition should be considered.

The second-generation antidepressants, ie Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake Inhibitors (SNRIs), are considered the first-line treatment options for depression in the elderly, because of their efficacy, 57 tolerability and safety profile. Except for paroxetine, they have lower anticholinergic effects than older antidepressants (ie tricyclics) and are thus well tolerated by patients with cognitive impairment or cardiovascular disease. SSRIs are also good for improving cognition, 58 while SNRIs are a good first choice in comorbid neuropathic pain. Most frequent SSRIs and SNRIs side effects include hyponatremia, 59 nausea and gastro-intestinal bleeding, 60 so periodic blood exams are recommended. Another second-generation antidepressant is mirtazapine that improves appetite being useful for anorexia, 61 and whose sedative side effect can be useful for insomnia. 62 A novel antidepressant, vortioxetine, a multimodal serotonin modulator, seems to be promising for elderly people since it also has a positive effect on cognition, independently of the improvement in depression. 63

When psychotic symptoms coexist, the addition of antipsychotics to antidepressants may be more effective than antipsychotics or antidepressants monotherapy, as reported by Meyers et al, 64 who found that the combination treatment of olanzapine plus sertraline was not only more effective than monotherapy but also equally tolerated.

Psychotherapy in Geriatric Depression

As for younger adults, also for older people psychotherapeutic approaches are to be encouraged, even in the presence of cognitive decline, since that treatment’s versatility gives the therapist the opportunity to adapt it to the patient’s needs and characteristics and to his/her physical and emotional environment.

In the following paragraphs a brief overview of the principal psychotherapy approaches available for older persons with depression is shortly provided.

Problem Adaptation Therapy (PATH)

PATH is a home-delivered psychosocial intervention, which has shown to lead to significant positive results in elderly with depression, by providing help in emotional regulation. 65 , 66 This kind of therapy puts the focus on strategies personalized on each patient’s needs (ie memory and organizational deficits, behavioral/functional limitations, interpersonal tension, social isolation and anhedonia). 65 PATH looks to lessen the negative impact of emotions by improving pleasurable activities, using a problem-solving approach and integrating environmental adaptations and compensatory strategies, for instance using calendars, checklists and strategies to sustain or shift attention.

Engage Therapy

This stepped therapy targets behavioral domains grounded on neurobiological constructs using simple and efficient behavioral techniques. 31 The intervention aims at modulating patient’s response using the “reward exposure” strategy, working on three main behavioral domains, ie “negativity bias” (negative valence system dysfunction), “apathy” (arousal system dysfunction), and “emotional dysregulation” (cognitive control dysfunction), and add strategies targeting these domains.

Problem Solving Therapy (PST)

PST is an 8-week intervention that consists in a seven-step process to solve problems, including problem orientation that directs patient attention to one problem at a time, problem definition that helps patients select relevant information to determine what the root problem is, goal setting that focuses attention to the desired outcome, brainstorming that helps patients consider different ways for reaching the goal, decision-making, to evaluate the alternative solutions likelihood and picking the best choice, and action planning that involves a step-by-step plan for the patient to implement his/her solution. 67

Supportive Therapy

This home-delivered psychotherapy focuses on nonspecific therapeutic factors as facilitating expression of affect, conveying empathy, highlighting successful experiences, and imparting optimism. Supportive Therapy reduces depression and disability in older patients with major depression, cognitive impairment, and disability. 65

Interpersonal Therapy

Interpersonal Therapy is a psychodynamic therapy that focuses on complicated grief, role transition, role dispute/interpersonal conflicts, and interpersonal deficits. 68 During the first phase of treatment, therapists help patients to explore and understand depressive symptoms through a psychoeducational approach. In later phases, problems are identified and understood in the interpersonal context. In the final phase, the therapist focuses on the gains and limitations of therapy and the prevention of relapses. 68

Computerized Cognitive Remediation (CCR)

CCR has demonstrated improvements in mood and self-reported function in depressed patients similar to those obtained through the Problem Solving Therapy. 81 CCR is suitable for patients with an MMSE score of at least 24/30. 68 It makes use of a video game to treat depression (EVO), personalized, self-administered and continuously adapted to the patients’ aptitude both at baseline and progress in treatment. 67 Unlike Problem Solving Therapy, the EVO participants showed generalization to untrained measures of working memory and attention, as well as negativity bias. CCR is relatively inexpensive and can be used at the patients’ homes, thus minimizing barriers to access of care, common in older adults. 31

Electroconvulsive Therapy (ECT)

An effective treatment for depression in elderly population, available from mental health specialists, is electroconvulsive therapy (ECT). 69 In ECT, an electrical stimulus is given for a brief period to produce a generalized seizure. The treatment is effective especially for psychotic depression, severe suicidality, treatment-refractory depression, catatonia, and depression with severe weight loss and anorexia, moreover, is indicated for older old (≥80 years). 70 A meta-analysis of the cognitive effects of ECT suggests its relative safety and the transient character of its effects on cognition. 71 Compared to antidepressants, ECT induces a higher speed of remission. 72

Practical Guidance for Depression Diagnosis and Treatment in the Elderly: A Pocket Guide for the Daily Clinical Management

If the proper recognition of geriatric depression remains at current challenge, the key aspects and main evidence presented here, along with a long interdisciplinary team clinical experience, lead to the identification of some guidelines to optimize the recognition and the adequate differential diagnosis of depression in the elderly. All the contents discussed below are summarized in the pocket guide, as a practical reference for a comprehensive diagnostic procedure in everyday clinical practice (see Figure 1 ).

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Pocket guide for the assessment and management of geriatric depression in everyday clinical practice.

Clinicians should carefully consider depression among possible differential diagnosis, particularly when: patients refer to their attention with vague complaints as pain, fatigue and diffuse symptoms and/or suffer from anxiety or sleep disturbances; some clues are evident, such as poor personal hygiene, flat affect and slumped posture; the patient tends to frequently use healthcare resources, as calls or visits to practitioners. 46 , 48

In these cases, an accurate screening for the underlying risk factors and a collection of anamnestic data, which include medical, psychological and cognitive remote and recent history, is crucial to evaluate all potential contributing or protecting factors. Furthermore, to assess the individual’s protective factors (that mainly deal with aspects related to social network, hobbies, physical activity or personal interests) will also have a positive clinical implication in the management and treatment of depressive symptoms from a non-pharmacological point of view, by knowing the activities that could be pleasant and stimulating, as well as his or her personal resources.

Moreover, caregivers and families can be helpful, since they may provide information about the patient’s mood, behavior and general functioning. In fact, they could notice relevant changes that are not reported by the patient, especially if she or he has poor insight, as in the case of the co-occurrence of cognitive impairment.

When talking to patients, instead, it is important to adequate to the social and cultural background of older adults. As discussed in the previous sections, they are not used to deal with mental health issues and to verbally express concerns about their mood. Thus, the clinician should prefer to use expressions such as “Are you feeling low/down?” instead of directly asking “Are you depressed?” in order to address the stigma, and discuss mental health referral in the broader context of other medical conditions to increase the acceptability. 38 At the same time, all the healthcare professionals should promote the sensitization of the elderly to mood disorders and more generally to mental health, so that they can themselves become more attentive and aware in recognizing their emotional and psychological difficulties.

Clinicians can count on several validated tools to quantitatively assess the presence and severity of depression, namely self-report scales, clinician rating scales and structured interviews. Despite their popularity and their clear advantages, some considerations have to be taken into account when dealing with older adults. First of all, these tools were mostly developed for young adults, so they do not always catch the appropriate features for the elderly. 73 This also falls on their validity and reliability, which are strictly related to the population they are based on. 74 Self-reports are widely used because of their quickness and ease of administration. However, they are susceptible to some respondent’s characteristics, such as low educational attainment or cognitive impairment, which can influence the true comprehension of questions or of the response format. 75 In general, in the case of older adults with cognitive impairment, it is preferable to avoid self-reports and use alternative assessment methods that include direct observation and family reports. 7 Moreover, especially for patients with comorbidities, items with somatic content may need further clarifications, since somatic symptoms could be misattributed to depression. 76 Lastly, visual impairment can obstacle the completion of self-report scales: in these cases, the clinician can either propose an enlarged copy of the scale or administrate it orally. The use of clinician rating scales overcomes some of these issues, since they are based on the direct observation of a trained professional. If clinician rating scales offer a more accurate measurement of depression, it has been found that they are less sensitive in detecting changes in mild forms of depression. 77 Structured interviews offer the possibility to facilitate the comprehension of questions, as well as to deeper investigate aspects that need to be better clarified, as the nature of somatic symptoms; however, because of the time and skills requested for their administration, their utility is limited. 78 Overall, there is no single superior assessment method; rather, it is important that clinicians are aware of their strengths and shortcomings and informed about the psychometric properties of the main tools, so that they can choose the most appropriate instrument depending on the characteristics of the individuals. Moreover, using multiple methods and sources of information (ie, multidimensional assessment) has been shown to be the most effective approach. 78

When depressive symptoms are detected and a diagnosis of LLD is probable, among all the other factors, also the domestic and family context has to be looked at, that is, whether there are dynamics that can exacerbate the depressive symptomatology of the patient. This could be the case, for example, of a dysfunctional interaction in the patient-caregiver dyad or of some psycho-affective characteristics of the caregiver himself (for example, if he or her is depressed as well), likewise tensions in family relationships or other health or financial issue of relevant psychological impact.

Lastly, it is important to exclude somatic causes of depression and to characterize a depressive episode or symptoms through patient history, clinical examination, laboratory tests, and/or imaging. In fact, LLD can per se be distinguished into a proper LOD or the recurrence of an EOD and, as stated, this has some clinical implications. Alternatively, depression can be secondary to a general medical condition or to a substance or medication use, considering that multimorbidity and polypharmacy are extremely common conditions among older adults. 79 Moreover, depressive symptoms could be the manifestation of a cerebrovascular disease or of a prodromal stage of AD, thus having a primarily organic origin. It is also important, in any case, to repeat when possible both the instrumental examinations (namely imaging techniques for the investigation of regional brain glucose metabolism, as FDG-PET) and the administration of cognitive and/or psychological screening tools in order to re-evaluate the overall diagnosis at a follow-up after 6–9 months. In fact, since LLD is a treatable and reversible condition, when a diagnosis of depression is made and a pharmacological or non-pharmacological treatment has been proposed, there should be evidence of efficacy. Otherwise, the question arises if the depressive symptoms observed were secondary to another cause (so, the diagnosis was incorrect) or the therapeutic approach chosen was not the most suitable one.

Depression and Cognitive Impairment: How to Address Differential Diagnosis?

Whereas depressive and cognitive disorders often coexist in the elderly, it is crucial to distinguish a geriatric depression that includes cognitive deficits from a mild dementia with depressive symptoms. What needs to be determined from a clinical point of view, in particular, is whether or not the picture observed will evolve into dementia.

Time is a first important criterion: while in the case of dementia symptoms will develop with a slow progression over several years, depressive symptomatology onset can be dated with more precision and the progression of symptoms is more rapid. 48 , 80 Another relevant cue concerns awareness. Patients with reversible dementia complain more about their cognitive disturbances, highlighting their failures and disability and precisely describing the pattern of their deficits; older adults with dementia, on the contrary, usually lack insight and their description of cognitive loss is vague. 80

From a neuropsychological point of view, evidence has been described about a different characterization of cognitive profiles of patients with AD and depression that can be striking in the differential diagnosis.

First of all, patients with LLD show a prominent dysexecutive profile, with a slight impairment in global cognition. 21 Conversely, a broader cognitive impairment, with significant deficits of orientation, language, praxis and memory is typical of AD. 81 Secondly, although a memory disturbance is visible in both AD and LLD, they have a different functional origin. The episodic memory impairment of AD, due to hippocampal damage, is defined by a recall deficit that does not improve with cueing or recognition testing, since storage processes are primarily affected. 82 Depression, instead, leads to an insufficient allocation of attentional resources and executive dysfunction that affect encoding or retrieval strategies, 83 without a pure storage deficit. Thus, a differential diagnosis can be made with specific memory testing based on effective and specific encoding of information and retrieval facilitation with cueing. 82 Inefficacy of cueing and a flat learning curve despite exposure is typical of AD, while an improvement with exposure and a normal recall with retrieval cues are distinctive features of depression. 36

In general, patients with depression have a suboptimal cognitive performance due to poor motivation that leads them to give up the task more easily, not pay enough attention and use ineffective strategies, so their overall performance is more influenced by the cognitive load of the task and the extent to which it relies on executive functions. 83

In addition to all the steps that have to be gone through, and the factors that have to be taken into account for a comprehensive assessment that includes depression among the differential hypothesis, some general guidelines are here suggested about organizational aspects that can be implemented to improve the detection of depressive symptoms in the elderly.

First, given the predominance of somatic symptoms in late-life depression, as well as their tendency to focus more on their physical (rather than mental) issues, it is plausible that older adults who suffer from depression do not spontaneously refer to a mental health professional at first, but to other figures, such as general practitioners, physicians or other health professionals. For this reason, it would be important to improve the knowledge about late-life depression presentation, as well as the capacity to carry out screening activities, of specialists of other disciplines. In fact, although a formal diagnosis of depression is not part of their role, they could improve the detection of potential cases because of their position, as it is the case of occupational and physical therapists, nurses or general practitioners. 45

Furthermore, different professional figures, as psychiatrists, geriatricians, psychologists and neuropsychologists, often have to interface with older adults’ depressive symptoms in the presence of multimorbidity and/or cognitive deficits, and thus answer questions concerning the differential diagnosis of depression. It is of paramount importance for each specialist to evaluate individuals in their whole complexity. In this regard, a multidimensional assessment should always be provided, in order to take into account all the aspects discussed above, such as risk and protective factors, medical and psychological history, social context and recent life events. Moreover, when appropriate, specialists should choose a multidisciplinary approach, referring patients to other professionals that can have a role in the differential diagnosis or in identifying the most appropriate therapeutic option. When possible, it would be a valuable resource for figures with different and complementary competences to work together.

For example, in the specific case of older adults with depressive symptoms with a subjective perception or signs of cognitive impairment, geriatricians and neuropsychologists could manage outpatient visits and consultations in wards together, considering the tangled characteristics of LLD discussed above. In this way, these professional figures can provide a first screening of cognitive functioning and the characterization of some deficits that will help in the differential diagnosis between depression and dementia. Moreover, this synergy can help to consciously investigate the presence of a mood disorder and, where necessary, to offer to the patient a more accurate psychological and cognitive assessment, targeted medical investigations and therefore a tailored treatment.

In case older adults are aware of having a mood problem, they mainly refer to the psychiatrist. Notwithstanding the crucial role and competence of psychiatrists in this context, it is still important for them to consider older adults in their whole complexity. In this regard, they should provide a multidimensional assessment that takes into account all the aspects previously stated (ie, risk and protective factor, medical and psychological history, social context, recent life events…) and, when appropriate, have a multidisciplinary approach, referring patients to other professionals that can have a role in the differential diagnosis or in identifying the most appropriate therapeutic approach.

Another professional figure that frequently has to cope with the differential diagnosis of depression are geriatricians, since in their clinical practice they consult with patients who show signs or have a subjective perception of cognitive or neuropsychiatric problems. Both in outpatient visits and in consultations in wards, it could be a valuable resource for the geriatricians to be assisted by a neuropsychologist. For the characteristics of LLD discussed above, it would be beneficial for patients if the geriatrician and the psychologist/neuropsychologist could work together in the assessment of older adults, both for the outpatient visits and for the consultation inwards.

In this way, these professional figures can synergistically provide a first screening of cognitive functioning and the characterization of some deficits that will help in the differential diagnosis between depression and dementia. Moreover, it can help to consciously investigate the presence of a mood disorder and, where necessary, to offer the patient a more accurate psychological and cognitive assessment, targeted medical investigations and therefore a tailored treatment.

In conclusion, as a general indication, it is overall important to periodically screen older adults for depression. Furthermore, patients who already are in treatment for depression need to be periodically re-evaluated, since the persistence of a depressive symptomatology suggests that the therapeutic approach chosen (pharmacological or not) should be revised.

Conclusions

This review, beyond reviewing depression, its clinical main characterizations and current challenges had the goal to propose a few guidelines born from the “every-day” clinical activity carried-out on this population. A “pocket guide” has been produced in order to hopefully orient clinicians in their daily clinical management of depression and in sensitizing different professionals to a comprehensive, global and multidisciplinary assessment of a complex disorder affecting complex individuals such as the elderly are. Shortly, after a first multidimensional assessment, clinicians are provided with clinical cues orienting their diagnostic process. Whereas the diagnosis of depression is confirmed, by also excluding other co-occurrent/different pathologies (ie cognitive decline), a first- and second-line therapeutic approaches are suggested, including both pharmacological and non-pharmacological options. Lastly, follow-ups and periodic clinical assessments are strongly recommended to monitor individuals over time.

Finally, by considering not only the risk, but also the protective factors that may help people in facing depression along late life, this review also indirectly encourages clinicians in promoting active social, cognitive and psycho-affective lifestyles in the elderly, as crucial, modifiable factors that may significantly influence the natural course of their aging.

The authors report no conflicts of interest in this work.

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