Utah has the highest rates of depression and suicide in the US, despite high rates of antidepressant prescriptions. People living at altitude are exposed to chronic hypobaric hypoxia, which may disrupt brain serotonin and bioenergetic function, to worsen depression and reduce selective serotonin reuptake inhibitor (SSRI) function. We therefore (1) used an animal model to study altitude-related depression, and (2) evaluated novel therapeutics in depressed Utah women.
We examined depression and SSRI function in rats housed at altitude. In treatment-resistant women, we tested antidepressant potential of compounds which correct hypoxia-induced brain deficits: creatine monohydrate (CrM) for bioenergetics or 5-hydroxytryptophan (5HTP) for serotonin deficit.
At altitude, female rats exhibit increased depression and lack of antidepressant response to SSRIs (except sertraline). In treatment-resistant women, adjunctive CrM and 5HTP+CrM improves depression status and bioenergetic function.
With significantly lower basal brain serotonin levels than men, women are likely more susceptible to altitude-related depression. Targeted treatment may be required: sertraline, CrM or 5HT-P+CrM show promise in improving mood and reducing suicidal ideation in women living at altitude or with hypoxic diseases.
Major depressive disorder (MDD) affects over 16.5% of the US population, with lifetime prevalence of up to 12% in men and 25% in women (Trivedi, 2008). Depression affects women more severely than men, potentially due to several biological and psychosocial mechanisms (Dalla, 2010). MDD is linked to poor serotonergic neurotransmission, and healthy women exhibit 52% lower rates of brain serotonin synthesis than men (Nishizawa, 1997), reduced serotonin receptor binding and higher excretion of serotonin metabolites (Dalla, 2010). Poor basal serotonin transmission may contribute to greater vulnerability to MDD in women.
Living at altitude may be linked to a brain serotonin deficit. Rats exposed to extremes of altitude (1-14 days, 20,000-25,000 ft) show reduced brain serotonin levels (Kumar, 2011). Serotonin is synthesized in two steps: the rate-limiting first step requires tryptophan hydroxylase 2 (TPH2) and molecular oxygen to convert tryptophan to 5-hydroxytryptophan (5HTP). 5HTP is then converted to serotonin in an oxygen-independent second step. Chronic hypobaric hypoxia decreases TPH2 activity, lowering levels of brain 5HTP and serotonin. Hypoxia may also compromise efficacy of selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed of antidepressants (Preskorn, 1996). SSRIs improve depression status by blocking the serotonin transporter to increase synaptic serotonin concentrations. However, in animal models of low brain serotonin, SSRIs can lose antidepressant efficacy (Durkin, 2008; Kulikov, 2011). By reducing brain serotonin, hypobaric hypoxia may thus simultaneously impair depression status and exacerbate SSRI-treatment resistance.
Living at altitude is also linked to brain hypometabolism. 1Hydrogen or 31Phosphorus-magnetic resonance spectroscopy (1H-MRS or 31P-MRS) scans allow in vivo measurement of brain bio-markers for cellular energy production (Kondo, 2011a). 1H-MRS neuroimaging of age- and gender-matched healthy residents living at moderate altitude (4,500 ft, Salt Lake City, UT) vs. those at sea level (Belmont, MA or Charleston, SC) identified a deficit in forebrain levels of the bioenergetic marker creatine (Cr) in those at altitude (Renshaw, 2012). A similar deficit in forebrain Cr was found in female rats after housing at an altitude of 10,000 ft for a week, implying that hypobaric hypoxia can induce this deficit (Bogdanova 2014). Cr plays an important role in regulating energy metabolism, and low Cr is representative of cellular hypometabolism
(Kondo, 2011a). A bioenergetic deficit is similarly seen in key depression-linked brain regions in MDD patients, which improves with effective treatment, but remains unchanged in non-responders (Iosifescu 2008). Living at altitude could thus increase vulnerability to MDD by causing brain deficits in serotonin and Cr levels.
Utah is representative of a high altitude state with significant burden of depression and suicidal behavior. Between 2000-2006, Utah exhibited the highest antidepressant prescription rates in the US: 18.4% vs. the US average of 10.8% (Cox, 2008). In Utah, 68% of antidepressants are prescribed for women, and >80% are for SSRIs (Gaskill, 2010). Despite this, Utah showed the highest depression index in the US in 2007, based on four criteria: annual percentage of adults and adolescents reporting a major depressive episode, adults reporting serious psychological distress, and rates of suicide (Mark, 2007). Over 30-40% of MDD patients taking anti-depressants do not respond adequately to treatment (Al-Harbi, 2012; Trivedi 2008), and treatment-resistance leads to unresolved depression, and increases suicidal ideation and suicide attempts. The Rocky Mountain States exhibit by far the highest rates of suicidal ideation (5.2% vs. 3.7%, CDC, 2011) and completed suicide (17.7 vs. 11.3 per 100,000) (Mark, 2007) in the US. Of particular relevance, the State of Utah had the highest annual prevalence of suicidal ideation in 2008-2009 (6.8%) – a rate that, incredibly, is more than three times that of Georgia, the US state with the lowest prevalence (2.1%) (CDC, 2011).
Moreover, Utah women contend with significantly greater burden of suicidal thoughts than men: 8.1% vs 5.6%, vs. the US average of 3.8% (women) vs. 3.5% (men) (CDC, 2011). Similarly, high rates of suicidal ideation are noted in women in the high-altitude States of Idaho (7%), Nevada (9%) and New Mexico (6%). Suicidal risk factors include cultural and socioeconomic factors (eg., poverty, rural residence, population density) as well as biological ones (eg., age, sex, mental illness), but depression is almost always observed in those who think about and attempt suicide. The poor quality of life inherent in 8% of Utah women expressing suicidal thoughts suggests a critical need for target-ed interventions for depression in this population. Here we first describe translational animal model studies of the impact of housing at altitude on depression-like behavior (DLB) and antidepressant function. Further, we describe clinical trials of non-traditional adjunctive treatments to correct hypoxia-linked neurochemical deficits in Utah women with TRD: with creatine monohydrate (CrM) to correct bioenergetics (Kondo 2016; Kondo, 2011) or with combination therapy of 5HTP+CrM to improve both serotonergic and bioenergetic deficits.
I. Animal Studies:
Male and female Sprague Dawley (SD) rats were received from Charles River (Raleigh, NC). All procedures were approved by the Institutional Animal Care and Use Committees of the University of Utah and the Veterans Affairs Salt Lake City Health Care System, and were performed in accordance to the NIH Guide for Care and Use of Laboratory Animals.
The altitude groups consist of sea level (SL), 4,500ft (4.5K) and 10,000ft (10K), plus a 20,000ft (20K) group in Study 1. Animals were housed in barometric chambers used to alter the ambient pressure at our facility (4,500ft): the hyperbaric chamber mimicked SL conditions (21% ppO2), and the hypobaric chamber mimicked 10K (15% ppO2) and 20K (10% ppO2), while the 4.5K group was housed at local conditions (18% ppO2) adjacent to the altitude chambers.
Forced Swim Test (FST):
The FST is a well-established test for DLB and antidepressant function, widely used in pre-clinical antidepressant development (Bogdanova, 2013).
After a week at altitude, rats were tested for DLB in the modified FST (Kanekar 2015). In the FST, a rat is placed in a clear tank (25cm diameter, 65cm tall) filled to 48cm deep water at 25oC (Detke, 1996), and behavior videotaped. The FST is conducted in 2 sessions: a conditioning pretest and 24hrs later, the test FST to assay for DLB.
In study 2, rats were injected with antidepressant or vehicle (C) at 1 hr, 19 hrs and 23 hrs after the pre-test FST (Detke 1996). Antidepressants were tested at optimal doses shown to be effective in the FST (Detke 1996): fluoxetine hydrochloride (Prozac®, 20mg/kg), paroxetine hydrochloride (Paxil®, 20mg/kg), escitalopram oxalate (Lexapro®, 20mg/kg), sertraline hydrochloride (Zoloft®, 10mg/kg), or the TCA desipramine hydrochloride (8mg/kg, positive control).
FST behavior is presented as percent time spent swimming, climbing or immobile. Latency to immobility (LTI) is the time taken to achieve the first 10 sec of immobility (Kanekar 2015). DLB in the FST is a measure of behavioral despair in response to the inescapable stress of forced swim (Bogdanova 2013). Increased immobility and a shorter LTI represent DLB in the FST, and antidepressants reduce immobility and increase LTI by ≥20%. Serotonergic antidepressants (SSRIs) improve DLB by increasing swimming, while noradrenergic/do-paminergic antidepressants (desipramine) increase climbing (Detke 1996).
Data was analyzed by two-way analysis of variance (ANOVA) to investigate effects of altitude and gender (Study 1), or altitude and treatment (Study 2). Data is presented as mean ± standard error of the mean (M±SEM). Statistical significance was determined at p<0.05, presented after Bonferroni corrections.
II. Clinical Trials
All studies were approved by the University of Utah Institutional Review Board.
Study 1. Dietary Cr in Treatment-Resistant Adolescent Females:
Participants were women between 13-20yrs of age with a primary diagnosis of MDD, with fluoxetine (Prozac®, open-label study) (Kondo, 2011) or equivalent SSRI dose (placebo-controlled study) (Kondo 2016) treatment for ≥8wks with ≥4wks at a dose of ≥40 mg/day, and a Children’s Depression Rating Scale-Revised (CDRS-R) raw score ≥40 at screening. Exclusion criteria included renal dis-ease, psychotic symptoms or active problematic use of alcohol or illicit drugs. Complete blood count, metabolic panel, and urinalysis were obtained at baseline and at study conclusion.
Treatment and Outcome Analyses:
In the open-label study, MDD patients received Creapure® brand CrM (AlzChem AG, Trostberg, Germany), 4g oral daily for 8wks (Kondo, 2011). In the placebo-controlled study, participants were randomly assigned to 2g, 4g or 10g CrM or placebo daily for 8wks (Kondo 2016). Vital signs and adverse signs were recorded at each visit. Rating scales administered were the CDRS-R, the Clinical Global Impressions scale-Severity (CGI-S) and the Columbia Suicide Severity Rating Scale (C-SSRS). The primary outcome was change in CDRS-R score from baseline. In vivo 31P-MRS neuroimaging was used to measure brain metabolites involved in cellular energy production, including Cr, phosphocreatine (PCr) and b-nucleotide phosphates (measuring adenosine triphosphate or ATP), vs. a baseline of total phosphate resonance (TP). 31P-MRS scans were conducted on participants prior to and after treatment, and on age-matched healthy control adolescents.
Study 2. Dietary 5HTP+Cr in Treatment-Resistant Adult Women:
Adult women were recruited with moderate-severe MDD at baseline as measured by Hamilton Depression Rating Scale (HAM-D) scores ≥16, with ≥8wks of treatment with an SSRI or serotonin norepinephrine reuptake inhibitor (SNRI) (Kious, 2017). Exclusion criteria included psychotic symptoms, seizure disorder and history of serotonin disorder.
Treatment and Outcome Analyses:
Open-label treatment consisted of dietary 5HT-P+CrM for 8wks, with visits at 1wk, 2wks, 4wks, 6wks and 8wks, and 2 post-treatment visits (10wks, 12wks). Participants received 5g of Creapure® and 100mg Fuller Enterprise’s 5HTP (Fuller En-terprise Inc., Ontario, Canada) daily for 8wks, to supplement ongoing SSRI/SNRI treatment. Study outcomes were measured by HAM-D, Montgomery-Asberg Depression Rating Scale (MADRS), CGI-S, and Beck Anxiety Inventory (BAI) scales. C-SSRS and Young Mania Rating Scale (YMRS) identified adverse effects. Since 5HTP is linked to serotonin syndrome and/or eosinophilia myalgia syndrome (Turner, 2006), subjects were screened at each visit. Blood tests were conducted at screening and follow up. Primary outcome was a change from baseline HAM-D scores. HAM-D, MADRS and BAI scores were analyzed by repeated-measures linear mixed model, with Sidak correction for multiple comparisons. Statistical significance was defined as p<0.05.
I. Animal Studies
Study 1. Altitude and Depression:
Rats were tested for DLB in the FST after a week of housing at SL, 4.5K, 10K or 20K (Kanekar 2015). For LTI, two-way ANOVA showed no effect of gender, a strong effect of altitude (p<0.0001) and of their interaction (F(3,88)=12.8, p<0.0001, Fig 1A, 1C). In females, LTI decreased significantly with altitude (F(3,44)=28, p<0.0001), but not in males. For immobility, a significant effect was seen of altitude (p=0.014) and of the interaction be-tween altitude and gender (F(3,88)=9.5, p<0.0001). Immobility increased significantly with altitude in females, but not males (F(3,44)=10.5, p<0.0001, Fig 1B, 1C). For swimming, a significant effect was seen of altitude (p=0.0005) and of its interaction with gender (F(3,88)=7.2, p=0.0002). In females, swimming decreased significantly with altitude (F (3, 44) = 11.8, p<0.0001), but climbing did not change (Fig 1C). Males were similar in FST behavior across groups (Fig 1C).
Study 2. Altitude and SSRI Function:
After housing for a week at SL, 4.5K or 10K, female rats were treated with the SSRIs fluoxetine, paroxetine, escitalopram or sertraline, or the TCA desipramine and tested for DLB in the FST (Fig 2) (Kanekar, 2018). For LTI, two-way ANOVA showed a main effect of treatment (p<0.0001), none of altitude (p=0.3) and a significant effect of their interaction (F(10,266)=2.4, p=0.009, Fig 2A). For immobility, significant effects were seen of antidepressant (p<0.0001), altitude (p=0.01) and their interaction (F(10,267)=1.97, p=0.03, Fig 2B). For swimming, significant effects were seen of treatment (p<0.0001) and altitude (p=0.0006), and of their interaction (F(10,267)=2.6, p=0.004, Fig 2C). For climbing, a significant effect was seen of antidepressant (p<0.0001), but none of altitude or their interaction (F(10,268)=0.8, p=0.67, Fig 2D). In post hoc analysis, fluoxetine, paroxetine and escitalopram did not improve LTI or immobility. Fluoxetine and escitalopram did not improve swimming, as expected of SSRIs in the FST, but paroxetine and sertraline did. Surprisingly, fluoxetine, paroxetine and escitalopram significantly decreased climbing. Sertraline was the only SSRI to exhibit strong antidepressant efficacy across altitude groups, significantly increasing LTI and decreasing immobility by improving both swimming and climbing, as previously documented (Page, 1999). Desipramine served as a good anti-depressant by augmenting climbing as previously seen (Detke 1996).
(1) Housing for a week at moderate altitudes (4.5K, 10K) incrementally increases DLB in female rats. (2) The SSRIs fluoxetine, paroxetine and escitalopram lose efficacy in female rats at altitude, while sertraline is functional at altitude. Desipramine also works at altitude, but cardiac toxicity and lethality in overdose limits its clinical use (Preskorn, 1996).
II. Clinical Trials
Study 1. Dietary CrM in Treatment-Resistant Adolescent Females:
Five patients completed 8wks of adjunctive CrM and 31P-MRS scans in the open-label study, with no adverse effects seen in vital signs, laboratory tests or behavior (Kondo, 2011). Mean CDRS-R score decreased by an average of 56% from 69±9 (M±SD) to 31±8 after treatment (Fig. 3A). After 8wks treatment, depressed adolescents exhibit a significant increase in forebrain PCr/TP (p=0.02, paired t-test) vs. healthy controls. Participants’ CDRS-R scores inversely correlated with the change in PCr/TP (p<0.04). Four of 5 MDD patients endorsed a history of suicidality: 4 had suicidal ideation, and two attempted suicide prior to this study. During treatment, two reported no suicidal ideation, while suicidal ideation resolved during the study in others, and remained absent at the 10wk follow-up visit.
In the placebo-controlled dose-ranging study, participants were randomized to receive placebo or CrM at 2g, 4g or 10g daily for 8wks (n=6-8/treatment). A drop in CDRS-R scores was seen across treatment groups (Kondo 2016). Pre- and post-treatment 31P-MRS scans revealed higher frontal lobe PCr/TP levels after CrM treatment, but not in placebo controls (Fig 3B): PCr/TP increased by 4.6% at the 2g dose, 4.1% with 4g, and 9.1% with 10g, while the placebo group showed a 0.7% drop. Lower depression scores correlated to higher forebrain PCr/TP (p<0.02, Fig 3C).
Study 2. Dietary 5HTP+CrM in Treatment-Resistant Adult Women:
Twelve women (average age of 34±11yrs) completed the study (Kious, 2017), 10 were on SSRIs and two were on SNRI. 5HTP+CrM was safe and well tolerated, with no evidence of serotonin syndrome, eosinophilia myalgia syndrome or other adverse effects. No treatment-emergent mania or hypomania (by YMRS scale) was seen, or nor was treatment-emergent suicidal ideation identified based on C-SSRS.
At baseline, participants exhibit moderate-severe MDD with mean HAM-D score of 19±2, MADRS score of 25±4 and CGI-S score of 4±0.3. After 8wks treatment, HAM-D scores reduced by 60% to an average of 7.5±4 (Fig 4A), with response criteria (≥50% reduction) met by 10 patients and remission criteria (score ≤7) met by 7 patients. Mean MADRS scores decreased by 65% to 9±6 (Fig 4B), with 12 patients meeting response criteria and 8 patients meeting remission criteria (score<10). Anxiety levels improved, with a 60% drop in BAI scores from 22.7±9 to 9.3±6 (Fig 4C). Depression severity in the CGI-S improved from 4.1±0.4 to 1.9±1. Significant improvements were seen within a week of treatment (p<0.00001, Fig 4).
(1) CrM supplementation of SS-RI-treated treatment-resistant adolescent women improved depression status and suicidal ideation over 8wks, paralleled with improved forebrain bio-energetics. (2) 5HTP+CrM augmentation of SSRI/SNRI-treated treatment-resistant adult women improved MDD and anxiety status, with a good safety profile.
In our animal model, housing at altitude induced increased depression in female rats (Kanekar 2015). Female rats at altitude did not respond to the SSRIs fluoxetine, paroxetine and escitalopram (Kanekar, 2018), which are primarily serotonergic (Damsa et al., 2004). The SSRI sertraline functioned well at altitude, potentially due to its ability to enhance dopaminergic as well as serotonergic neurotransmission (Kanekar, 2018; Page 1999). In recent studies, rat brain serotonin levels decrease with housing at altitude, particularly in the striatum and prefrontal cortex, brain regions involved in mood regulation (C.S. Sheth, unpublished observations). We also find that anxiety and anhedonia (the inability to derive pleasure from pleasurable activity) increase in female rats at altitude (Sheth, 2018). These studies thus suggest that living at altitude or with chronic hypoxic diseases may decrease brain serotonin levels to worsen the status of depression and anxiety disorders, and may also render SSRIs ineffective.
Since SSRIs form over 80% of the US market for antidepressants and anxiolytics, this likely worsens rates of unresolved mood disorders at altitude, and may be responsible for the heightened rates of suicidal ideation seen in women in the Rocky Mountain States. Given the significantly lower basal brain serotonin in women vs. men, women living at altitude or with chronic hypoxic disorders may be particularly vulnerable to worsened mood and SSRI treatment-resistance. Women in the high-altitude Rocky Mountain States, Utah included, may thus suffer from unresolved mood disorders despite attempts to medicate with antidepressant use, thus suggesting the need for novel non-traditional therapeutics for altitude-related mood disorders.
We therefore conducted clinical trials of compounds directed at improving altitude-related deficits in bioenergetics (CrM) and serotonin (5HTP). Supplementing CrM in SSRI-resistant adolescent women improved depression status and brain bioenergetics (Kondo 2011, 2016). Improving brain bioenergetics is proposed as a mechanism for enhancing antidepressant response (Iosifescu 2008), and dietary CrM was initially shown to improve brain bioenergetics in healthy adults (Lyoo, 2003). Also, CrM augmentation of escitalopram-treated women improved SSRI response vs. escitalopram+placebo (Lyoo 2012). CrM treatment may thus enhance brain bioenergetics, to hasten antidepressant response and enhance clinical remission in depressed women. Our current study suggests that CrM improves response and remission criteria in TRD women. Additionally, CrM-linked enhancement in fore-brain PCr/TP correlates with improved depression scores, suggesting a mechanism of action (Kondo 2016). A placebo-controlled study of 10g CrM for treatment-resistant adolescent women is currently in process.
Our study of 5HTP+CrM augmentation in depressed treatment-resistant adult women is the first trial of combination therapy simultaneously targeting bioenergetics and serotonin synthesis (Kious, 2017). The intermediate metabolite in serotonin synthesis, 5HTP is readily converted to serotonin (Turner 2006). In clinical trials, dietary 5HTP showed antidepressant efficacy in an aver-age of 56% of MDD patients within 2-4wks (Turn-er 2006). Our clinical trial is a small scale open-la-bel study without placebo control, yet it suggests that 5HTP+CrM therapy may be a feasible new approach to TRD in women. A placebo-controlled study of 5HTP+CrM is currently in progress in SSRI/SNRI-resistant adult women.
These clinical studies show that novel antidepressant therapeutics targeted to improving hypoxia-related brain deficits in bioenergetics and serotonin may serve as more effective antidepressants for those living at altitude or with chronic hypoxic diseases.
While the consequences of extreme high altitude exposure (>18,000ft) have been studied for decades with regards to mountaineering, only recently has living at moderate altitudes (2000ft-10,000ft) been suggested to impact human mood and quality of life (Brenner, 2011; Maa, 2010). The human brain consists of about 2% of our body weight, but utilizes 20% of the body’s energy at rest. With the high basal oxygen needs of the brain, neurological symptoms including headaches, sleep disruption and mood disorders are prevalent in the chronic hypoxia experienced at altitude (Maa, 2010). As more people move to reside or vacation at moderate altitudes, addressing the physiological consequences of long-term altitude exposure becomes critical. The studies we describe here are an initial effort to understand the impact of living at moderate altitudes, such as in Utah, Colorado, and the other Rocky Mountain states, on brain physiology, mood status and anti-depressant function.
Hypoxia exposure can alter brain neurochemistry to promote biomarkers for depression and suicidal behavior (Gould, 2017). In animal models, hypoxia disrupts neurotransmitter balance, increases inflammation and cell stress, and lowers metabolic function in key brain regions involved in mood disorders (Gould, 2017; Kumar, 2011). In animal models, hypoxia is linked to low brain serotonin levels. Low brain serotonin in humans is implicated in greater depression, anxiety, impulsivity, risk-taking behavior and aggression, each of which is also linked to suicidal behavior. Further studies with our animal model may thus be of high relevance in studying hypoxia-related brain and behavioral deficits which may alter susceptibility to suicidal behavior, and, combined with clinical trials, will help us critically evaluate novel potential therapeutics for MDD in chronic hypoxia.
Chronic hypoxia exposure may worsen MDD and impair antidepressant function. With greater vulnerability to hypoxia, women living at altitude or with chronic hypoxic diseases likely suffer from a greater burden of MDD-linked health issues, poor quality of life and suicidal ideation, suggesting a critical need for effective antidepressant interventions in this population. Targeted therapeutics may be required for depressed women at altitude: the current studies identify sertraline, adjunctive CrM or 5HTP+CrM as promising antidepressant therapeutics for women exposed to chronic hypoxia. Given the high rates of depression and suicidal behavior documented in women living in the high-altitude Rocky Mountain States, the success of these studies are likely to be of considerable beneficial impact.
- Al-Harbi, K. S. (2012). Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence, 6, 369-388. doi:10.2147/PPA.S29716
- Bogdanova, O. V., Abdullah, O., Kanekar, S., Bogdanov, V. B., Prescot, A. P., & Renshaw, P. F. (2014). Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia. Behav Brain Res. doi:10.1016/j.bbr.2014.01.027
- Bogdanova, OV, Kanekar, S., D’Anci, K, & Renshaw, P.F. (2013). Factors influencing behavior in the forced swim test. Physiol Behav, 118, 227-239. doi:10.1016/j.physbeh.2013.05.012
- Brenner, B., Cheng, D., Clark, S., & Camargo, C. A., Jr. (2011). Positive association between altitude and suicide in 2584 U.S. counties. High Alt Med Biol, 12(1), 31-35. doi:10.1089/ham.2010.1058
- CDC. (2011). Suicidal Thoughts and Behaviors Among Adults Aged ≥18 Years, United States, 2008–2009. Morbidity and Mortality Weekly Report, Centers for Disease Control and Prevention, 60(13).
- Cox, E., D. Mager, E. Weisbart. (2008). Geographic variations in drug use: 2000-2006.
- Dalla, C., Pitychoutis, P. M., Kokras, N., & Papadopoulou-Daifoti, Z. (2010). Sex differences in animal models of depression and antidepressant response. Basic Clin Pharmacol Toxicol, 106(3), 226-233. doi:10.1111/j.1742-7843.2009.00516.x
- Damsa, C., Bumb, A., Bianchi-Demicheli, F., Vidailhet, P., Sterck, R., Andreoli, A., & Beyenburg, S. (2004). “Dopa mine-dependent” side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry, 65(8), 1064-1068. 29
- DelMastro, K., Hellem, T., Kim, N., Kondo, D., Sung, Y. H., & Renshaw, P. F. (2011). Incidence of major depressive episode correlates with elevation of substate region of residence. J Affect Disord, 129(1-3), 376-379. doi:10.1016/j.jad.2010.10.001
- Detke, M. J., & Lucki, I. (1996). Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth. Behav Brain Res, 73(1-2), 43-46.
- Durkin, S., Prendergast, A., & Harkin, A. (2008). Reduced efficacy of fluoxetine following MDMA (“Ecstasy”)-induced serotonin loss in rats. Prog Neuropsychopharmacol Biol Psychiatry, 32(8), 1894-1901. doi:10.1016/j.pnpbp.2008.09.008
- Gaskill. (2010). Antidepressant use in Utah.
- Goodwin, R. D., Kroenke, K., Hoven, C. W., & Spitzer, R. L. (2003). Major depression, physical illness, and suicidal ideation in primary care. Psychosom Med, 65(4), 501-505.
- Gould T.D., Brenner LA, Brundin L, Can A, Courtet P, Donaldson Z, Dwivedi Y, Guillaume S, Gottesman II, Kanekar S, Lowry CA, Renshaw PF, Rujescu D, Smith E, Turecki G, Zanos P, Zarate CA, Zunszain PA, Postolache TT. (2017). Animals models to improve our understanding and treatment of suicidal be- havior. [Review]. Translational Psychiatry 7:e1092. Doi:10.1038/tp.2017.50.
- Haws, C. A., Gray, D. D., Yurgelun-Todd, D. A., Moskos, M., Meyer, L. J., & Renshaw, P. F. (2009). The possible effect of altitude on regional variation in suicide rates. Med Hypotheses, 73, 587-590. doi:10.1016/j. mehy.2009.05.040
- Iosifescu, D. V., Bolo, N. R., Nierenberg, A. A., Jensen, J. E., Fava, M., & Renshaw, P. F. (2008). Brain bioenerget- ics and response to triiodothyronine augmentation in major depressive disorder. Biol Psychiatry, 63, 1127-1134. doi:10.1016/j.biopsych.2007.11.020
- Kanekar, S., Bogdanova, O. V., Olson, P. R., Sung, Y. H., D’Anci, K. E., & Renshaw, P. F. (2015). Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not in males. High Alt Med Biol, 16(1), 52-60. doi:10.1089/ham.2014.1070
- Kanekar, S., Sheth CS, Olson PR, Bogdanova OV, Ombach H, M Petersen, Renshaw CE, Sung YH, D’Anci KE, Ren shaw, PF (2018). Hypobaric Hypoxia Exposure in Rats Differentially Alters Antidepressant Efficacy of the Selective Serotonin Reuptake Inhibitors Fluoxetine, Paroxetine, Escitalopram and Sertraline. Pharmacol Biochem Behav, 170: 25-35. Doi:10.1016/j.pbb.2018.05.002.
- Kim, N., Mickelson, J. B., Brenner, B. E., Haws, C. A., Yurgelun-Todd, D. A., & Renshaw, P. F. (2011). Altitude, gun ownership, rural areas, and suicide. Am J Psychiatry, 168(1), 49-54. doi:10.1176/appi.ajp.2010.10020289
- Kious, B. M., H. S., Young-Hoon Sung, Douglas G. Kondo, Perry Renshaw. (2017). An open-label pilot study of creatine monohydrate and 5-hydroxytryptophan for SSRI- or SNRI-resistant depression in adult women. J. Clinical Psychopharmacol 37:578-583. Doi:10.1097/JCP00000000000000754
- Kondo, D. G., Forrest, L. N., Shi, X., Sung, Y. H., Hellem, T. L., Huber, R. S., & Renshaw, P. F. (2016). Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids, 48(8), 1941-1954. doi:10.1007/ s00726-016-2194-3
- Kondo, D. G., Hellem, T. L., Sung, Y. H., Kim, N., Jeong, E. K., Delmastro, K. K., Renshaw, P. F. (2011a). Review: magnetic resonance spectroscopy studies of pediatric major depressive disorder. Depress Res Treat, 2011, 650450. doi:10.1155/2011/650450
- Kondo, D. G., Sung, Y. H., Hellem, T. L., Fiedler, K. K., Shi, X., Jeong, E. K., & Renshaw, P. F. (2011). Open-label ad junctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. J Affect Disord, 135(1-3), 354-361. doi:10.1016/j.jad.2011.07.010
- Kulikov, A. V., Tikhonova, M. A., Osipova, D. V., Kulikov, V. A., & Popova, N. K. (2011). Association between tryp tophan hydroxylase-2 genotype and the antidepressant effect of citalopram and paroxetine on immobility time in the forced swim test in mice. Pharmacol Biochem Behav, 99(4), 683-687. doi:10.1016/j.pbb.2011.06.020 Kumar, G. K. (2011). Hypoxia. 3. Hypoxia and neurotransmitter synthesis. Am J Physiol Cell Physiol, 300(4), C743-751. doi:10.1152/ajpcell.00019.2011
- Lyoo, I. K., Kong, S. W., Sung, S. M., Hirashima, F., Parow, A., Hennen, J., . . . Renshaw, P. F. (2003). Multinuclear tation of creatine-monohydrate. Psychiatry Res, 123(2), 87-100.
- Maa, E. H. (2010). Hypobaric hypoxic cerebral insults: the neurological consequences of going higher. NeuroReha bilitation, 26(1), 73-84. doi:10.3233/NRE-2010-0537
- Mark, T. L., D.L. Shern, J.E. Bagalman and Z. Cao. (2007). Ranking America’s Mental Health: An Analysis of Depression Across the States Mental Health America.
- Nishizawa, S., Benkelfat, C., Young, S. N., Leyton, M., Mzengeza, S., de Montigny, C., Diksic, M. (1997). Differ- ences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci U S A, 94(10), 5308-5313.
- Page, M. E., Detke, M. J., Dalvi, A., Kirby, L. G., & Lucki, I. (1999). Serotonergic mediation of the effects of fluoxe- tine, but not desipramine, in the rat forced swimming test. Psychopharmacology (Berl), 147(2), 162-167.
- Preskorn, S. (Ed.) (1996). Clinical Pharmacology of SSRIs. Caddo, OK: Professional Communications.
- Renshaw, P., A. Prescot, D. Ongur, R. Huber, D. Yurgelun-Todd (2012). Suicide and brain chemical changes with altitude. International Society for Affective Disorders Abstracts.
- Sheth, C., Ombach, H., Olson, P., Renshaw, P. F., & Kanekar, S. (2018). Increased Anxiety and Anhedonia in Female Rats Following Exposure to Altitude. High Alt Med Biol. doi:10.1089/ham.2017.0125
- Trivedi, M. H., & Daly, E. J. (2008). Treatment strategies to improve and sustain remission in major depressive disorder. Dialogues Clin Neurosci, 10(4), 377-384.
- Turner, E. H., Loftis, J. M., & Blackwell, A. D. (2006). Serotonin a la carte: supplementation with the serotonin pre cursor 5-hydroxytryptophan. Pharmacol Ther, 109(3), 325-338. doi:10.1016/j.pharmthera.2005.06.004
- Webb, R. T., Kontopantelis, E., Doran, T., Qin, P., Creed, F., & Kapur, N. (2012). Suicide risk in primary care patients with major physical diseases: a case-control study. Arch Gen Psychiatry, 69(3), 256-264. doi:10.1001/archgenpsychiatry.2011.1561
- Young, S. N. (2013). Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: possible role of hypoxia causing decreased serotonin synthesis. J Psychiatry Neurosci, 38(6), 423-426. doi:10.1503/jpn.130002
Kanekar S & Renshaw P. (2019). The Impact of Living at Altitude on Depression and Anti-depressant Function in Utah Women: The Need for Novel Antidepressants. Utah Women’s Health Review. doi: 10.26054/0KY1QCF4E1.