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. Author manuscript; available in PMC: 2025 Oct 1.
Published in final edited form as: J Affect Disord. 2024 Jul 14;362:416–424. doi: 10.1016/j.jad.2024.07.025

Effects of Open-Label Transdermal Nicotine Antidepressant Augmentation on Affective Symptoms and Executive Function in Late-Life Depression

Patricia Andrews 1,*, Jennifer N Vega 1,*, Sarah M Szymkowicz 1, Paul Newhouse 1,2, Rachel Tyndale 3, Damian Elson 1, Hakmook Kang 4, Sarah Siddiqi 1, Elizabeth B Tyner 1, Kathleen Mather 1, Faith M Gunning 5, Warren D Taylor 1,2
PMCID: PMC11373687  NIHMSID: NIHMS2018625  PMID: 39009312

Abstract

Background:

Late-life depression (LLD) is characterized by a poor response to antidepressant medications and diminished cognitive performance, particularly in executive functioning. There is currently no accepted pharmacotherapy for LLD that effectively treats both mood and cognitive symptoms. This study investigated whether transdermal nicotine augmentation of standard antidepressant medications benefitted mood and cognitive symptoms in LLD.

Methods:

Nonsmoking participants aged 60 years or older with unremitted LLD on stable SSRI or SNRI medications (N=29) received transdermal nicotine patches up to a 21mg daily dose over 12 weeks. Clinical measures assessed depression severity, secondary affective symptoms, and cognitive performance. Nicotine metabolite concentrations were obtained from blood samples.

Results:

Depression severity significantly decreased over the trial, with a 76% response rate and 59% remission rate. Change in depression severity was positively associated with nicotine exposure. Participants also exhibited improvement in self-reported affective symptoms (apathy, insomnia, rumination, and generalized anxiety symptoms), negativity bias, and disability. Executive function test performance significantly improved, specifically in measures of cognitive control, as did subjective cognitive performance. Adverse events were generally mild, with 75% of the sample tolerating the maximum dose.

Conclusion:

The current study extends our previous pilot open-label trial in LLD, supporting feasibility and tolerability of transdermal nicotine patches as antidepressant augmentation. Although preliminary, this open-label study supports the potential benefit of transdermal nicotine patches for both mood and cognitive symptoms of LLD. Further research, including definitive randomized, blinded trials, is warranted to confirm these findings and explore long-term risk and benefit.

Trial Registration:

The study was registered with clinicaltrials.gov (NCT04433767).

INTRODUCTION

Late-life depression (LLD), or major depressive disorder in individuals aged 60 years and older, encompasses a diverse range of emotional, cognitive, and physical symptoms (Szymkowicz et al., 2023a; Taylor, 2014). LLD is more common in medically ill and cognitively impaired populations and is associated with a poor response to conventional antidepressants, with a meta-analysis reporting a pooled remission rate of 32.6% in placebo-controlled trials (Dew et al., 2007; Nelson et al., 2008). Similar to observations in younger populations, pharmacological augmentation benefits treatment-resistant depression, resulting in remission rates of 28% (Lenze et al., 2023). LLD’s resultant morbidity and mortality requires innovative, accessible treatments (Szymkowicz et al., 2023a; Taylor, 2014).

Beyond mood symptoms, many individuals with LLD also exhibit diminished cognitive performance (Szymkowicz et al., 2023b), particularly executive dysfunction (Alexopoulos, 2019; Szymkowicz et al., 2023a). Executive dysfunction includes difficulty with planning, problem-solving, and sustained attention, and negatively affects functional ability and quality of life. Poorer cognitive performance, particularly poorer executive function, is associated with poor response to antidepressant medications (Alexopoulos, 2019; Szymkowicz et al., 2023a). While cognitive performance may improve with effective treatment, patients typically do not achieve age-adjusted normative performance levels (Bhalla et al., 2006; Sexton et al., 2012; Sheline et al., 2006) and LLD is associated with increased risk for dementia (Diniz et al., 2013). There is currently no established pharmacotherapy for LLD that effectively treats both mood and cognitive symptoms.

The nicotine acetylcholine receptor (nAChR) may be a viable pharmacological target for depression (Gandelman et al., 2018b; Zurkovsky et al., 2013). Animal models demonstrate that nicotine, a nonselective nAChR agonist, can ameliorate depressive-like behavior (Semba et al., 1998; Tizabi et al., 1999; Vazquez-Palacios et al., 2004). High prevalence of smoking among depressed individuals suggests that some may use nicotine as self-medication (Markou et al., 1998). Preliminary trials examining nonsmoking midlife depressed adults suggest that nicotine reduces the severity of depressive symptoms (Haro and Drucker-Colin, 2004; McClernon et al., 2006; Salin-Pascual and Drucker-Colin, 1998). Our previous pilot trial observed similar benefit in 15 nonsmoking individuals with LLD, demonstrating a response rate of 86.7% and a remission rate of 53.3% (Gandelman et al., 2018a), rates comparable to those seen with approved antidepressants in LLD (Roose and Schatzberg, 2005; Sneed et al., 2008). We further observed improvements in measures of apathy, rumination, and negativity bias (Gandelman et al., 2018a).

As the cholinergic system plays a pivotal role in mediating cognitive changes observed in both normal aging and dementia (Dumas and Newhouse, 2011), nicotine administration may benefit cognitive performance. Initial investigations into the nAChR system employed blockade paradigms, revealing that antagonists like mecamylamine impair cognitive processes including learning, memory, psychomotor speed, and attention (Newhouse et al., 1994; Vitiello et al., 1997). Conversely, nAChR agonists may enhance cognitive performance in these domains (Gandelman et al., 2018b; Heishman et al., 2010). Nicotine may be particularly beneficial and improve performance in impaired populations on more effortful tasks (McClernon et al., 2003; Potter and Newhouse, 2004). Our prior trial suggested that nicotine benefits episodic memory and working memory in LLD (Gandelman et al., 2018a).

This study examined whether transdermal nicotine augmentation of existing antidepressants safely benefitted mood and cognitive symptoms in nonsmoking patients with LLD. We hypothesized participants would exhibit improvement in the primary outcome of depression severity, as well as secondary outcomes including affective symptom measures, negativity bias, and subjective and objective cognitive performance, particularly in executive function. We additionally explored the relationship between change in clinical measures and blood nicotine metabolite concentrations in order to probe biological activity and potentially provide preliminary information on exposure levels related to clinical change.

METHODS

Participants

Participants were recruited at Vanderbilt University Medical Center (Nashville, Tennessee) from clinical referrals and community advertisements from December 2020 through June 2022. Inclusion criteria required age 60 years or older, meeting DSM5 criteria for a current episode of Major Depressive Disorder, single episode or recurrent, with a baseline Montgomery-Asberg Depression Rating Scale (MADRS)(Montgomery and Asberg, 1979) severity of ≥15. Participants were required to be fluent in English with a Mini-Mental State Exam (MMSE)(Folstein et al., 1975) score of ≥ 24. Participants had to be on a stable, therapeutic dose for at least 6 weeks of an allowed SSRI or SNRI medication (fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, or vilazodone).

Exclusion criteria included (1) history of psychosis or other psychiatric diagnoses, except for anxiety symptoms occurring in depressive episodes; (2) alcohol or substance use disorder of moderate severity or greater in the last year; (3) any use of tobacco or nicotine in the last year; (4) living with a current smoker; (5) acute suicidality; (6) acute grief; (7) primary neurological disorders, including dementia; (8) MRI contraindications; (9) electroconvulsive therapy or transcranial magnetic stimulation in last two months; and (10) current or planned psychotherapy. The presence of Mild Cognitive Impairment was not exclusionary.

Participants were excluded for regular use of medications with central cholinergic or anticholinergic effects or inhibitors of CYP2A6, the primary enzyme involved in the metabolic inactivation of nicotine (Supplemental Table 1). Prohibited antidepressant medications included bupropion, paroxetine, tricyclic antidepressants or monoamine oxidase inhibitors.

All participants provided written informed consent. The study was approved by the Vanderbilt University Medical Center Institutional Review Board. The study was registered with ClinicalTrials.gov (NCT 04433767).

Study Visits and Clinical Assessments

After baseline assessments, participants were seen every 3 weeks over the 12-week trial. Following a three-week dose taper, participants completed a final 15-week post-study safety assessment.

Diagnostic and medical assessments:

The Mini-International Neuropsychiatric Inventory for DSM5 (MINI; version 7.0.2)(Sheehan et al., 1998) assessed diagnoses of lifetime depression and psychiatric disorders. Diagnoses and duration of the current depressive episode were confirmed by interview with a study clinician, either a geriatric psychiatrist or psychiatric mental health nurse practitioner. The Antidepressant Treatment History Form (ATHF)(Keller et al., 1987) quantified the intensity of the current antidepressant regimen and intensity of all antidepressant trials of the current depressive episode. The ATHF scores all antidepressant medications from 1–4, including both primary antidepressants and adjunctive antipsychotic medications approved for depression. Higher scores indicate higher doses and a score of 4 equates to a maximum dose for that medication. Allowed adjunctive medications, such as sedatives, are scored as a 1. Medication anticholinergic burden was assessed using the Anticholinergic Cognitive Burden (ACB) Scale (Boustani et al., 2008). Medical burden was quantified using the Cumulative Illness Rating Scale-Geriatric (CIRS-G)(Miller et al., 1992) and self-reported disability with the World Health Organization Disability Assessment Schedule (WHODAS) 2.0.

Depression severity was assessed by a study clinician administering the MADRS every three weeks. Exploratory affective symptom self-report questionnaires were completed at baseline, week 6, and week 12. These assessed anhedonia (Dimensional Anhedonia Rating Scale, DARS) (Rizvi et al., 2015), apathy (Apathy Evaluation Scale, AES) (Marin et al., 1991), anxiety (Generalized Anxiety Disorder 7-item, GAD-7; and Anxiety Sensitivity Index-3, ASI-3) (Taylor et al., 2007), fatigue (Fatigue Severity Scale, FSS) (Krupp et al., 1989), insomnia (Insomnia Severity Index, ISI) (Bastien et al., 2001), rumination (Ruminative Response Scale, RRS) (Nolen-Hoeksema et al., 1993), and worry (Penn State Worry Questionnaire, PSWQ) (Meyer et al., 1990). We reverse-scored the DARS so that across all scales, higher scores indicate greater symptom severity.

Self-referential negativity bias was assessed every three weeks using an adapted version of the Trait Adjectives Task (Harmer et al., 2004; Tranter et al., 2009). Participants viewed a series of randomized, rapidly presented positive and negative characteristics and quickly indicated whether each adjective did or did not apply to them. Positive and negative adjectives are balanced and selected from a normed list, matched for word length and arousal (Anderson, 1968). Measures include number of items endorsed or rejected, and reaction time for those trials.

Study Drug Administration

Like our previous report (Gandelman et al., 2018a), transdermal nicotine (TDN) was administered using an unblinded rigid dose escalation strategy. Participants applied the study patch each morning after waking and showering and removed the patch at bedtime, for a goal of 16 hours of daily administration. They rotated the patch application location to reduce the risk of skin irritation. They started on 3.5mg (half of a 7mg patch) in week 1, increasing to 7mg in weeks 2 and 3, 10.5mg (half of a 21mg patch) in weeks 4–6, 14mg in weeks 7–9, and 21mg in weeks 10–12. Doses were reduced if participants could not tolerate the higher dose. After trial completion, doses were tapered and discontinued over a final 3 weeks. Study clinicians and participants were blinded to nicotine and metabolite concentrations.

Neuropsychological Assessments

Neuropsychological testing was conducted at baseline and at week 12, focusing on cognitive domains relevant to LLD and aging.

  • Executive Function: Executive function was measured using the NIH EXAMINER computerized test battery (Kramer et al., 2014). The EXAMINER battery assesses executive functions, including: a) Inhibition, using a Flanker task; a Continuous Performance Test; and an antisaccade eye movement task; b) Working Memory, using a dot counting task and the N-back task; c) Set Shifting, using a stimulus matching and set shifting task; d) Fluency, assessing phonemic and category fluency; e) Planning, using an unstructured task; and f) Insight, where participants rate their perceived performance. The EXAMINER battery’s primary outcome is its Executive Composite score. Secondary outcomes include factor scores of Cognitive Control, Fluency, and Working Memory.

  • Psychomotor Speed: For the Choice Reaction Time task, participants hold a button until a light appears above one of several other buttons, then move to push that button as quickly as possible. This measures both response and psychomotor speed.

  • Episodic Memory: The Selective Reminding Task assessed immediate and delayed verbal memory via an 8-trial, 16-word test (Buschke, 1973). Missed items on each recall trial are repeated before the next attempt. A delayed recall trial is administered 20 minutes later.

Participants completed self-report questionnaires of perceived cognitive function, including the PROMIS Applied Cognition Abilities questionnaire (Howland et al., 2017) and the Attentional Control Scale (ACS) (Judah et al., 2014).

Measurement of Nicotine and Nicotinic Metabolites

Participants had 10ml of blood drawn every 3 weeks to measure metabolites including nicotine, cotinine, and 3-hydroxycotinine. Cotinine and 3-hydroxycotinine are inactive metabolites that can be summed (COT+3HC) to provide a better marker of longer-term nicotine exposure than nicotine blood concentrations alone, and to reduce the impact of variation in cotinine formation and removal by genetically variable CYP2A6. Blood draws occurred after at least 2 weeks on a stable dose, and approximately 4 hours after patch application, allowing for participants to be at approximately steady-state concentrations (Gorsline et al., 1993). Samples were stored at −70 degrees until analyzed at the University of Toronto using LC-tandem mass spectrometry (Tanner et al., 2015).

Statistical Analyses

Analyses were conducted in R Statistical Software (version 4.3.2). Data from all available assessments were used, including either 5 (MADRS score, clinical assessments), 3 (participant questionnaires), or 2 (neuropsychological tests) measurement points. Analyses of clinical outcomes measured at 3 or 5 time points were conducted using linear growth models using nlme version 3.1–163 (Pinheiro et al., 2023), and the fixed effect estimate of time evaluated the linear trajectory of scores across the study. Each model included age and gender as time-invariant effects, and time and subject ID were defined as random nested effects to account for within-subject and within-time heterogeneity. Subsequent growth models included MADRS as a time-varying predictor or examined the effect of nicotine metabolite exposure on MADRS score and vital sign measures across the trial. All tests of statistical significance were adjusted for multiple comparisons using the False Discovery Rate (FDR) correction (Benjamini and Hochberg, 1995). Statistical significance was defined as a FDR corrected p-value of ≤ 0.05.

Neuropsychological data analyses used individual linear regression models. Dependent variables were change scores (i.e., week 12 score – week 0 score) and included mean-centered baseline scores for age and education and contrast coded biological sex as covariates. The intercept represented the average change in scores and evaluated whether score changes were statistically significant across the trial. We similarly adjusted for multiple outcomes using FDR correction. For test measures exhibiting a statistically significant change over time, we examined the effect of nicotine metabolite exposure as an additional independent variable.

Prior to analyses, nicotine concentrations were assessed for outliers at each time point, defined as data points above of the upper inner fence (Q3 + 1.5 × IQR) or below the lower inner fence (Q1 – 1.5 × IQR). Outliers were identified across timepoints for nicotine concentrations (5 observations across 142 total measures) and COT+3HC concentrations (2 observations across 142 total measures). Models including metabolite concentrations were compared using raw data and data without outliers. Since results remained consistent, statistics reported are from models without outliers for less biased estimates. EXAMINER scores were assessed to meet recommended data integrity thresholds (composite standard error < 0.75).(Staffaroni et al., 2020) No participant exceeded the threshold, so all EXAMINER data were retained.

RESULTS

Sample Characteristics

After telephone screening of 115 individuals, 34 participants provided written informed consent (CONSORT Diagram, Figure 1). Four were excluded for not meeting a minimum depression severity by MADRS and one withdrew consent, resulting in 29 participants starting study drug. Seventy-nine percent (N=23) were women, with a mean age of 68.1y (SD=4.8, range 60–78y). Two reported being black, one being multiracial, and the remainder white, with none being of Hispanic backgrounds. Participants were highly educated, with a mean 16y of education (SD=2.18), and cognitively intact on screening, with a mean MMSE score of 29.1 (SD=0.7, range 28–30), Medical morbidity was common (detailed in Supplemental Table 2), with a mean CIRS-G score of 11.2 (SD=3.8, range 4–20), but with only limited use of anticholinergic medications (mean ACB score of 0.8, SD=1.0, range 0–3).

Figure 1.

Figure 1.

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CONSORT Diagram

One participant withdrew after completing week 6 assessments due to adverse events. All other participants completed the 12-week trial.

The sample was moderately depressed, with a mean baseline MADRS score of 23.8 (SD=4.2, range 16–40). Mean age of initial depressive episode onset was 32.7y (SD=19.8y, range 7–76y). Participants continued previously prescribed antidepressant medications, including SSRIs (citalopram = 1, fluoxetine = 1, escitalopram = 3, sertraline = 6) or SNRIs (desvenlafaxine = 4, duloxetine = 7, venlafaxine = 7; full list with doses in Supplemental Table 3). Including limited use of allowed sedative/hypnotics, the mean ATHF score for antidepressants used at baseline was 3.9 (SD=1.5, range 2–7), while the mean ATHF score for all treatments received in the current depressive episode was 4.9 (SD=3.0, range 2–15).

Retention and Nicotine Exposure

All participants completed the study, except one who withdrew after week 6 due to study drug tolerability. Approximately 75% of participants reached the maximum study dose of 21mg (N=22). A minority of participants only tolerated 7mg (N=2), 10.5mg (N=3), or 14mg (N=2) doses. End of study mean nicotine concentration was 15.00 ng/ml (SD=7.89, range 4.22–29.96 ng/ml), mean cotinine concentration was 159.28 ng/ml (SD=89.92, range 44. 41–458.48 ng/ml) and mean 3-hydroxycotinine concentration was 94.28 ng/ml (SD=66.74, range 8.48–337.92ng/ml). These are comparable to concentrations observed in studies of smokers utilizing similar nicotine patch doses (Benowitz et al., 2002; Lawson et al., 1998). For context, lighter (10–15 cigarettes per day) to heavier (> 30 cigarettes per day) smokers exhibit mean peak nicotine concentrations ranging from 13 to 24 ng/ml (Lawson et al., 1998).

We observed a significant increase over time in nicotine concentrations (ß=1.19, SE=0.13, t=9.47, df=108, p<0.0001) and COT+3HC concentrations (ß=19.44, SE=2.10, t=9.47, df=110, p<0.0001) (Figure 2, Panels B and C). The effect of time was no longer statistically significant when dose was added to the model, as dose was itself significantly associated with nicotine concentrations (ß=0.66, SE=0.20, t=3.39, df=107, p=0.0010) and COT+3HC concentrations (ß=12.61, SE=2.83, t=4.46, df=109, p<0.0001). Only three individuals exhibited isolated concentrations of nicotine or COT+3HC that were lower than expected for the patch dose compared to other participants. These occurred mid-study, not at study endpoint.

Figure 2.

Figure 2.

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Change in depression severity and nicotine metabolite levels

Figure 2.A displays change in depression severity by MADRS (Montgomery Asberg Depression Rating Scale) score over time. Figures 2.B and 2.C display change in nicotine concentrations (ng/ml) and cotinine + 3-hydroxycotinine concentrations (COT+3HC; ng/ml) over time, excluding outlier values. Mean values displayed with a horizontal bar, while the box displays the interquartile range. Error bars display the upper and lower values of data within the outlier range, defined as 1.5x the interquartile range.

Mood and Affective Outcomes

Participants exhibited a mean MADRS score reduction of 15.76 points (SD=6.7) with a response rate (> 50% improvement) of 76% and remission rate (final sustained MADRS ≤ 8) of 59% (Table 1). Most individuals who responded or remitted did so by week 6. We observed a statistically significant decrease over time in our primary outcome of depression severity by MADRS score (Table 2, Figure 2A). Reduction in depression severity was significantly associated with increased nicotine exposure measured by patch dose (ß=−0.50, SE=0.20, df=112, t=−2.54, p=0.0124), nicotine concentrations (ß=−0.34, SE=0.09, df=107, t=−3.81, p=0.0002), and 3HC+COT concentrations (ß =0.02, SE=0.01, df=109, t= 3.17, p=0.0020). At the time of response, responders exhibited a mean nicotine concentration of 10.19 ng/ml (SD=6.45) and mean 3HC+COT concentration of 150.59 ng/ml (SD=89.10), values similar to those observed in smokers receiving a 15mg patch (Benowitz et al., 2002).

Table 1.

Response and remission rates by study visit

Time (weeks) MADRS change Response Rate Remission Rate
3 −8.5 (5.5) 9 (31.0%) 7 (24.1%)
6 −12.2 (6.7) 17 (58.6%) 14 (48.3%)
9 −13.3 (7.5) 18 (62.0%) 16 (55.2%)
12 −15.8 (6.7) 22 (75.9%) 17 (58.6%)
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Montgomery-Asberg Depression Rating Scale (MADRS) score change presented as mean difference (standard deviation) from baseline. Response rate defined as number of participants (percentage of sample) who sustained > 50% reduction in MADRS score from baseline. Remission rate defined as number of participants (percentage of sample) who sustained MADRS score of 8 or less.

Table 2.

Primary and Secondary Affective Outcomes.

Descriptive Statistics Linear Mixed Effect Model Results
Measure Baseline Week 12 Mean Change Estimate SE 95% CI Corrected p value
Depression (MADRS) 23.79 (4.21) 8.04 (5.98) −15.76 (6.70) −1.22 0.12 −1.46, −0.97 0.002
Anxiety Sensitivity (ASI-3) 21.15 (14.96) 15.12 (10.55) −6.03 (10.86) −0.09 0.55 −1.05, 1.23 0.876
Anxiety Symptoms (GAD7) 7.79 (4.39) 4.42 (3.58) −3.37 (3.37) −0.22 0.06 −0.33, −0.11 0.002
Anhedonia (DARS) 20.07 (12.69) 14.87 (9.35) −5.20 (10.47) −0.18 0.17 −0.52, −0.16 0.326
Apathy (AES) 43.38 (10.23) 35.24 (9.03) −8.14 (8.91) −0.63 0.14 −0.92, −0.34 0.002
Fatigue (FSS) 45.17 (11.11) 40.88 (11.64) −4.29 (14.00) −0.3 0.22 −0.74, 0.13 0.235
Insomnia (ISI) 14.90 (5.58) 9.88 (5.91) −5.01 (7.36) −0.41 0.12 −0.65, −0.18 0.002
Rumination (RRS) 28.38 (10.41) 18.60 (11.60) −9.78 (12.27) −0.74 0.20 −1.15, −0.32 0.002
Worry (PSWQ) 47.93 (15.80) 41.71 (16.78) −6.22 (22.39) −0.47 0.35 −1.17, 0.23 0.235
Trait Adjectives Task
Good items endorsed (N) 14.75 (4.53) 16.92 (5.08) 2.17 (5.55) 0.17 0.08 0.01–0.33 0.041
Bad items rejected (N) 16.29 (3.72) 18.58 (3.99) 2.29 (4.87) 0.18 0.09 0.01–0.35 0.041
Good items endorsed (RT) 484.01 (202.27) 369.73 (208.61) −114.28 (228.89) −11.13 3.36 −17.81, −4.45 0.002
Bad items rejected (RT) 538.91 (212.81) 384.40 (206.31) −154.51 (252.25) −12.64 3.68 −19.94, −5.33 0.002
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Models adjusted for age, gender, and time. Statistics presented for time. Values presented as mean (standard deviation). Higher scores indicate greater symptom severity. Statistical significance was defined as an FDR corrected p-value of ≤ 0.05. Degrees of freedom (df) for analyses were: MADRS = 113df, other affective outcomes = 52df, trait adjectives measures = 93df. ASI-3 = Anxiety Sensitivity Index-3; AES = Apathy Evaluation Scale; DARS = Dimensional Anhedonia Rating Scale; FSS = Fatigue Severity Scale; GAD7 = Generalized Anxiety Disorder 7 scale; ISI = Insomnia Severity Index; MADRS = Montgomery Asberg Depression Rating Scale; PSWQ = Penn State Worry Questionnaire; RT = Reaction Time, in milliseconds; RRS = Ruminative Response Scale.

We observed changes in secondary self-report affective symptoms (Table 2), including statistically significant decreases in apathy, insomnia, rumination, and anxiety symptoms. We did not observe significant changes in anhedonia, fatigue, worry, or anxiety sensitivity. In models including depression severity, symptom scores were significantly associated with MADRS score, but time effects on symptom change were no longer statistically significant (Supplemental Table 4).

We also observed a reduction in self-referential negativity bias with the Trait Adjectives Test (Table 2). Participants endorsed significantly more positively valenced adjectives and rejected significantly more negatively valenced adjectives. We observed similar significant reductions in reaction time to endorse positive adjectives and reject negative adjectives. However, when MADRS scores were added to the model, independent effects of time were no longer statistically significant (Supplemental Table 4).

Neuropsychological Test Outcomes

We observed a statistically significant improvement in the NIH EXAMINER’s executive composite measure, primarily driven by an improvement in the cognitive control factor (Table 3). We also observed significant improvement in subjective cognitive performance using the PROMIS Applied Cognition Scale and in subjective attentional function using the ACS. The EXAMINER fluency and working memory factors did not demonstrate a statistically significant change over the study period, nor did we observe statistically significant changes in CRT or SRT measures. In exploratory models, we did not observe statistically significant relationships between any exposure measure (dose, nicotine concentration, COT+3HC concentration) and difference in the EXAMINER’s executive composite or cognitive control factors (data not shown).

Table 3.

Secondary Cognitive Outcomes

Descriptive Statistics Linear Regression Results
Measure Baseline Week 12 Mean Change Estimate SE 95% CI T value Corrected p value
NIH Examiner
• Executive composite 0.41 (0.42) 0.57 (0.41) 0.16 (0.31) 0.18 0.07 0.04, 0.32 2.70 0.0318
• Cognitive Control Factor 0.29 (0.66) 0.60 (0.45) 0.31 (0.50) 0.34 0.08 0.17, 0.51 4.08 0.0050
• Fluency Factor 0.43 (0.42) 0.60 (0.58) 0.18 (0.52) 0.19 0.11 −0.04, 0.42 1.70 0.1712
• Working Memory Factor 0.09 (0.70) 0.12 (0.61) 0.03 (0.69) 0.09 0.13 −0.18, 0.37 0.71 0.6057
Continuous Recognition Test (CRT)
• CRT, total 996.79 (137.08) 997.67 (162.40) 0.88 (123.40) 9.04 25.77 −44.28, 62.36 0.35 0.8100
• CRT, recognition 546.67 (66.24) 521.85 (64.61) −24.82 (65.92) −21.78 12.76 −48.17, 4.60 −1.71 0.1712
• CRT, motor 450.12 (92.52) 475.82 (126.59) 25.70 (93.28) 31.28 21.01 −12.19, 74.75 1.49 0.2146
SRT, total recall 54.69 (13.27) 55.26 (11.27) 0.57 (16.61) −0.25 2.43 −5.28, 4.78 −0.10 0.9196
Subjective Cognitive Performance Questionnaires
Descriptive Statistics Linear Mixed Effect Model Results
Attentional Control Scale 47.48 (9.23) 54.27 (8.86) 6.79 (9.96) 0.52 0.14 0.21, 0.83 4.03 0.0067
PROMIS Applied Cognition Abilities 18.83 (5.78) 24.50 (7.83) 5.67 (8.27) 0.43 0.13 0.17, 0.69 3.35 0.0067
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Models adjusted for age and gender, values presented as mean (SD). Neuropsychological testing measures also adjusted for education. Statistical significance was defined as an FDR corrected p-value of ≤ 0.05. Degrees of freedom (df) for neuropsychological tests were 24df, with 51df for subjective performance questionnaires. CRT = choice reaction time; SRT = selective reminding task

Disability Outcomes

Participants reported decreased disability on the WHODAS (mean change=−14.04; SD=15.81; ß=−1.10, SE=0.27, 95% CI = −1.65, −0.55, df=56, p=0.001). In models adjusting for depression severity, WHODAS score was positively associated with MADRS score (ß=0.92, SE=0.25, 95% CI=0.41, 1.42, df=55, p=0.001), but independent effects of time were no longer statistically significant (ß=0.08, SE=0.42, 95% CI = −0.76, 0.91, df=55, p=0.850).

Safety and Tolerability

Cardiovascular vital signs did not significantly change across the trial. These include changes in pulse rate (mean=1.79 beats per minute, SD=12.94; ß=0.11, SE=0.19, df=112, t=0.57, p=0.5675), systolic blood pressure (mean=−3.17 mmHg, SD=17.74; ß=−0.26, SE=0.29, df=112, t=−0.89, p=0.3732), or diastolic blood pressure (mean=−0.43 mmHg, SD=13.62; ß=−0.02, SE=0.17, df=112, t=−0.12, p=0.9038). However, we observed a significant but modest decrease in mean weight (−4.00 lbs [−1.81 kg], SD=7.34; ß=−0.39, SE=0.10, df=112, t=−3.86, p=0.0002). Neither patch dose nor 3HC+COT concentrations were significantly associated with weight change (data not shown). Higher nicotine concentrations were associated with greater weight loss (ß=−0.02, SE=0.01, df=111, t=−2.71, p=0.0078), while the independent effect of time on weight loss persisted (ß=−0.36, SE=0.10, df=111, t=−3.63, p=0.0004).

Most adverse events were expected, including patch site reactions (pruritus or slight rash; N=11), lightheadedness or dizziness (N=6), and nausea (N=5). Less common side effects (occurring in 2–3 participants) included headache, increased dream activity, difficulty with sleep onset, and feelings of tension. Adverse events primarily occurred at the 14mg or higher dose. For the seven participants who could not tolerate the maximum patch dose, dose-limiting adverse events included lightheadedness / dizziness (N=2), nausea (N=3), and increased tension (N=2). We observed higher nicotine concentrations at week 6 in participants who experienced dose-limiting adverse events (Supplemental Materials: Results). The only serious adverse event was a non-emergent hospitalization for an elective surgery that was not study related.

Participants were assessed for safety after completing the dose taper, three weeks past the primary study endpoint. Participants denied adverse events, withdrawal symptoms, or nicotine cravings after discontinuing study patches.

DISCUSSION

This report largely replicates our previous open-label trial in LLD (Gandelman et al., 2018a), supporting possible clinical benefit and tolerability of transdermal nicotine patches. It extends past work by focusing on transdermal nicotine patches as an augmentation approach to ongoing SSRI or SNRI treatment, which would be the likely role of nicotine patches if efficacy is established in definitive trials. We observed a relationship between clinical improvement in our primary depression outcome and nicotine exposure. However, most individuals exhibiting a clinical response did so in the first 6 weeks at lower nicotine metabolite concentrations than seen at the final titrated maximum dose. Beyond observing improvement across a range of affective symptoms, negativity bias, and disability, participants exhibited improvement in executive function, specifically cognitive control.

The observed clinical response rate (76%) and remission rate (59%) is comparable to our previously reported response and remission rates of 86.7% and 53.3% (Gandelman et al., 2018a). This is consistent with findings in other adult cohorts where nicotine administration improved depressive symptoms (Haro and Drucker-Colin, 2004; McClernon et al., 2006; Salin-Pascual and Drucker-Colin, 1998). A novel finding is that reduction in depression severity is associated with increased nicotine exposure, although most individuals who responded to nicotine patches did so at relatively lower levels of exposure than achieved by the final titration. This suggests that the higher titrated doses (e.g., 21mg) may not be needed to obtain clinical benefit.

Secondary affective outcomes replicated prior findings that nicotine administration improved apathy, rumination and self-referential negativity bias (Gandelman et al., 2018a), extending these benefits to insomnia and generalized anxiety symptoms. However, scores on measures of anxiety sensitivity, anhedonia, fatigue, and worry were lower at study completion than baseline (Table 2), the observed changes were not statistically significant. Further work is needed to determine if this reflects differences in what affective symptoms are influenced by nicotine, or whether this is an artifact of limited power related to our sample size.

Nicotine administration also benefitted cognitive performance (Gandelman et al., 2018b; Zurkovsky et al., 2013). Our previous study suggested that nicotine may improve subjective cognition and modestly benefit episodic memory and working memory. While we observed improvement in subjective cognitive symptoms, the current study did not replicate past objective findings. Instead, we observed improvement in overall executive function, driven by improvement in cognitive control. Discrepancies across studies may reflect heterogeneity in study samples or different neuropsychological measures, as the current battery was selected to more specifically interrogate executive functions. Notably, the finding of improvement in cognitive control is consistent with our proposed model that nicotine may benefit LLD by modulating the cognitive control network (Gandelman et al., 2018b). However, we did not observe an association between change in executive function and nicotine exposure. It is possible that the study’s dose titration schedule and resultantly high final nicotine and metabolite concentrations may have obfuscated a threshold effect wherein a lower exposure level provided benefit. Additionally, longer durations of exposure may be needed to observe broader changes in cognition.

As demonstrated previously (Gandelman et al., 2018a; Newhouse et al., 2012; White and Levin, 2004), transdermal nicotine was well tolerated. We observed stability in vital signs, except, similar to our prior reports, a modest weight reduction(Gandelman et al., 2018a; Newhouse et al., 2012). However, participants with higher nicotine concentrations tended to experience more adverse events, with adverse events becoming more frequent at the 14mg dose. This tolerability issue did not appear to limit the clinical response, as lower doses resulted in response and remission (Table 1). This suggest that lower doses may effectively treat depression while being better tolerated.

Although replicating and expanding our previous findings, there are limitations including the open-label trial design. Given high rates of placebo responses in antidepressant trials, the gold-standard for demonstrating efficacy is through a randomized trial. Moreover, antidepressant response rates in LLD are higher in open-label studies compared to placebo-controlled trials (Sneed et al., 2008). Other limitations include the relative lack of racial and ethnic diversity, limiting the generalizability of our findings. Moreover, the sample exhibited normal cognitive performance on screening with MMSE. We may have observed greater change in cognitive performance measures had the sample exhibited greater baseline variability in performance. This trial enrolled a relatively small sample size, which limits the study power and may have influenced our results. Future studies investigating transdermal nicotine in blinded, controlled trials would provide important information on potential interrelations between changes in nicotine exposure, clinical improvement, cognitive performance change, and subjective cognitive ability and disability. Moreover, if clinical benefit is supported, maintenance studies may be needed to assess potential longer-term risks. However, parallel work in a population with Mild Cognitive Impairment supports that nicotine patch administration is safe for up to six months (Newhouse et al., 2012).

In conclusion, this study expands the literature supporting that pharmacological agonist activity of nAChRs may benefit mood and cognitive symptoms in LLD, potentially by influencing key intrinsic networks facilitating attention and executive function (Gandelman et al., 2018b). Definitive placebo-controlled trials are needed, and long-term safety of transdermal nicotine patches needs to be confirmed. This study supports further investigation of the use of transdermal nicotine in the treatment of depression in older adults. particularly when used at lower than maximal doses as augmentation.

Supplementary Material

Supplemental Material

Acknowledgements:

This study was supported by the National Institute of Mental Health grants R61 MH122464 and R33 MH122464 and UL1 TR000445 from NCATS/NIH. Dr. Tyndale acknowledges her Canada Research Chair.

Footnotes

Disclosure of Conflicts of Interest

The authors report no conflicts of interests, including no conflicts with any product mentioned or concept discussed in this article.

Previous Presentations

These data have been presented in part at the American Association for Geriatric Psychiatry 2023 Annual Meeting on March in New Orleans, LA, USA on March 6, 2023.

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