|Year : 2017 | Volume
| Issue : 1 | Page : 8-16
The Safety, efficacy, and tolerability of pharmacological treatment of depression in patients with cardiovascular disease: A look at antidepressants and integrative approaches
Laura Chang1, Nina Liu2
1 Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, USA
2 Department of Psychiatry and Behavioral Neuroscience, University of Chicago; Department of Psychiatry, Northshore University Health System, Chicago, Illinois, USA
|Date of Web Publication||24-May-2017|
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry, Northshore University Health System, Chicago, Illinois
Source of Support: None, Conflict of Interest: None
Patients with cardiovascular disease (CVD) are at an increased risk of developing psychiatric illnesses, particularly depression. Depression is an independent risk factor leading to a cardiac event, which has been shown in patients with or without known coronary artery disease (CAD). Treatment of depression has been shown to improve quality of life and result in a better cardiovascular prognosis in patients with comorbid CVD. However, pharmacological treatment of depression in this particular patient population is not without risk and is not always effective. An emerging approach to improve nonresponse to antidepressants is the use of adjunctive nutraceuticals. This article is to review the pharmacological options for treating depression in patients with CAD. The use of integrative approaches and supplements in patients with CVD is also discussed.
Keywords: Alternative approaches, antidepressants, coronary artery disease, depression
|How to cite this article:|
Chang L, Liu N. The Safety, efficacy, and tolerability of pharmacological treatment of depression in patients with cardiovascular disease: A look at antidepressants and integrative approaches. Heart Mind 2017;1:8-16
|How to cite this URL:|
Chang L, Liu N. The Safety, efficacy, and tolerability of pharmacological treatment of depression in patients with cardiovascular disease: A look at antidepressants and integrative approaches. Heart Mind [serial online] 2017 [cited 2022 Jul 2];1:8-16. Available from: http://www.heartmindjournal.org/text.asp?2017/1/1/8/206968
| Introduction|| |
Much has been written regarding the interrelated nature of cardiovascular disease (CVD) and psychiatric illnesses. Patients with CVD are at an increased risk of developing psychiatric illnesses, particularly depression.,, Untreated psychiatric illnesses in patients with underlying cardiopathology lead to poor follow-up, decreased medication adherence, poor compliance with prescribed exercise regimens, and poor diet.,, Specifically, Stewart et al. reported that patients who were identified to have depressive symptoms were more likely to endorse symptoms of angina, dyspnea or claudication, worse overall health, more frequent unemployment, increased isolation, and/or adverse life events (P < 0.05). In addition, endothelial dysfunction, inflammation, hypercoagulation, and neuroendocrine dysregulation secondary to untreated psychiatric illnesses are hypothesized to also play a role in CVD development/exacerbation. Morbidity and mortality in CVD patients with untreated psychiatric illnesses significantly increase, with Chung et al.'s finding that depressed patients not receiving an antidepressant had a 4.1 times higher risk of death and hospitalization than nondepressed patients on antidepressants. Evidence exists that appropriate treatment of underlying psychiatric illnesses might reduce the subsequent cardiovascular morbidity and mortality. However, pharmacological treatment of psychiatric illnesses in patients with CVD is not without risks. Consequences of psychotropic intervention include adverse drug effects such as weight gain, hyperlipidemia or hypertension (HTN), drug–drug interactions, and even direct cardiac effects such as delayed repolarization. In addition, an increasingly pertinent issue in psychiatry in recent years is that of the limitations of conventional antidepressants, with two-thirds of people treated with first-line antidepressants not achieving remission. As such, an emerging approach to improve nonresponse to antidepressants is the use of integrative approaches. A number of novel therapeutic approaches have been considered to ameliorate depressive symptoms, including changes in lifestyle and diet. Developing treatments targeted toward the heterogeneity of depression is not only required for improved quality of life among individuals with major depressive disorder (MDD) but also remains an important aspect of translating more recent findings, produced from the brain–mind–body trichotomy, into clinical practice.
Given the significant comorbidity between CVD and depression as well as the ability to reduce cardiac mortality if the depression is properly treated, it is imperative that providers are familiar with safe and effective ways to adequately treat this disorder in this at-risk population. The focus of this article is to explore the pharmacological options for treating patients with comorbid depression and CVD. The use of antidepressants and supplements in patients with CVD will be discussed. Of note, nonpharmacological interventions such as cognitive behavior therapy, cardiac rehabilitation, exercise training, and psychosocial rehabilitation  also have significant evidence in decreasing psychiatric symptoms in this population., However, these treatment modalities are outside the scope of this article.
| Antidepressants|| |
Monoamine oxidase inhibitors
Due to the risk of hypertensive crisis and their tendency to elevate blood pressure, monoamine oxidase inhibitors (MAOIs) are typically avoided in patients with CVD. If used, careful attention should be paid to dietary intake of tyramine-containing foods as well as avoiding the use of other sympathomimetic agents. Although there is evidence that transdermal selegiline at doses at or below 6 mg/24 h may not require avoidance of tyramine-rich foods, safe use of this medication in the CVD population has not been evaluated. Teply et al. recommended that MAOIs should be avoided in patients with HTN, and caution that orthostatic hypotension is also a troublesome side effect that further limits the use of MAOIs in this population.
Tricyclic antidepressant (TCA) use in patients with underlying CVD has fluctuated over the past 40 years. Initial studies regarding the safety TCAs used in patients with CVD were promising. Several studies , demonstrated that therapeutic doses of TCAs did not impair left ventricular function, even in patients with congestive heart failure. Shores et al. also demonstrated that even in patients with impaired left ventricular function at baseline, both doxepin and imipramine were effective in treating depression and did not have a negative inotropic effect. In 1977, Bigger et al. reported the antiarrhythmic effect of imipramine hydrochloride. Further studies demonstrated that, at therapeutic levels, TCAs suppress arrhythmias, functioning in a similar manner as Class I antiarrhythmic drugs. TCAs prolong interventricular conduction secondary to sodium channel blockade, which results in a decrease in the frequency of premature ventricular contractions. This discovery led investigators to hypothesize that the antiarrhythmic effect of TCAs could be of particular benefit to depressed patients with preexisting arrhythmias. However, results from the cardiac arrhythmia suppression trial (CAST) led to reconsideration of this theory. The CAST trials sought to determine whether treatment of postmyocardial infarction (MI) ventricular irritability with an antiarrhythmic resulted in decreased mortality. However, these studies were discontinued prematurely after it was demonstrated that treatment with a Type IC or IA antiarrhythmic in post-MI patients actually resulted in increased mortality, possibly secondary to an interaction between the antiarrhythmic drug and ischemic myocardium. Given that TCAs have a Class I antiarrhythmic action similar to the antiarrhythmics utilized in the CAST trials, it is not unreasonable to assume that TCAs might carry the same risk of increased mortality in this population. Later research demonstrated that TCAs decrease all component measures of heart rate variability and increase QT variability, which are associated with ventricular fibrillation and sudden cardiac death. It does not appear that the effect of TCAs on cardiac conduction varies within the class but is instead more dependent on the severity of the patient's preexisting CV condition.
In addition to their antiarrhythmic effect, TCAs also pose particular challenges in individuals with cardiac failure due to their increased risk for postural hypotension. The risk for marked postural hypotension rises from around 10%–15% in healthy patients to 50% in patients with heart failure. This side effect occurs with all TCAs, but to a lesser extent in nortriptyline. Further complicating the use of TCAs in patients with CVD is the fact that treatment with TCAs results in significantly higher systolic and diastolic blood pressure than controls. Finally, TCAs have been found to increase resting heart rate by 10–20 beats/min upon initiation, with some improvement as tolerance develops. However, even after using imipramine for 1 year, Shrivastava et al. noted an average increase of 5–10 beats/min. The increased cardiac workload may precipitate angina in patients with ischemic heart disease (IHD) or lead to decompensation of cardiac failure.
In summary, the use of TCAs in patients with CVD is relatively contraindicated. However, if a TCA must be used, Mavrides and Nemeroff identify nortriptyline as the preferred medication due to its lower incidence of orthostatic hypotension. Still, when comparing nortriptyline to a selective serotonin reuptake inhibitor (SSRI) in patients with CVD, nortriptyline had more adverse cardiovascular events and decreased overall tolerance when compared to paroxetine  or fluoxetine, but with similar efficacy between the TCA and SSRI. As such, unless there is convincing evidence to utilize a TCA in this population, they are best to be avoided.
Selective serotonin reuptake inhibitors
SSRIs as a class offer numerous advantages compared to the earlier antidepressants. To begin, SSRIs do not slow cardiac conduction or cause orthostatic hypotension, have only a rare incidence of HTN (1%–2%), and overall are much better tolerated in terms of side effects compared to TCAs and MAOIs. In addition, depressed patients may have enhanced platelet activation and aggregation mediated through hyperactive platelet 5-HT2A receptor signal transduction system. SSRIs block platelet 5-HT2A receptors, and thus decrease the amount of serotonin stored by the platelets, resulting in less serotonin release during platelet aggregation. Because of this effect, SSRIs are proposed to have antithrombotic properties, which may be cardioprotective. A meta-analysis done by Mazza et al. demonstrated that in patients recovering from acute coronary syndromes (ACS), SSRIs use significantly lowered rates of re-hospitalizations from all causes. However, in patients at risk for hemorrhage, such as those who are also taking an antiplatelet or anticoagulant, SSRIs could increase risk of bleeds. Castro et al. demonstrated that antidepressants with higher serotonin affinity were associated with more gastrointestinal (GI) bleeds. SSRIs with the highest affinity for the serotonin transporter include paroxetine, sertraline, escitalopram, and fluoxetine. SSRIs can also increase gastric acidity, which in turn further increases the risk of a GI bleed. As such, Teply et al. suggest that for patients who are taking an SSRI and antiplatelet therapy, providers consider coadministration of a proton-pump inhibitor as well as the use of an SSRI with lower serotonin affinity. Finally, several studies have demonstrated that the use of SSRIs in patients with comorbid CVD and depression can result in decreased rate of rehospitalization and improvement in prognosis.,
Although SSRIs as a whole have fewer drug–drug interactions compared to older generation antidepressants due to their more selective mechanism of action and receptor profile, several interactions are still notable. Teply et al. compiled excellent tables of both inhibitory effects of second-generation antidepressants on cytochrome P450 enzymes as well as pertinent pharmacodynamics interactions. Interactions of particular gravity include those that occur with fluoxetine or fluvoxamine. Specifically, there is an increased risk of bleeding when fluoxetine or fluvoxamine is combined with warfarin, even beyond the baseline combined antiplatelet activity, due to their inhibition of CYP2C9 and thus the potential for increased levels of warfarin., Severe bradycardia and heart block have been reported when metoprolol or propranolol were combined with fluoxetine, thought to be due to fluoxetine's inhibition of CYP2D6., The inhibition of CYP2D6 also carries the risk of decreased clearance of class 1C antiarrhythmic agents, such as flecainide or propafenone. Finally, because of their CYP2C19 inhibition, fluoxetine and fluvoxamine should not be combined with clopidogrel, as this could reduce its antiplatelet effect.
Several studies have been done on specific SSRI use in patients with CVD. Roose et al. demonstrated that both nortriptyline and fluoxetine improved depressive symptoms in patients with cardiac disease, with no difference in efficacy, but fluoxetine did not exhibit the cardiovascular side effects that were observed in nortriptyline (increase in heart rate, increase in supine blood pressure, decrease in ejection fraction)., In another double-blind, placebo-controlled trial of fluoxetine, which looked at patients with depression and recent MI, the authors concluded that fluoxetine was both safe and effective in patients with a recent MI.
In a study done comparing the safety and efficacy of paroxetine to nortriptyline in patients with depression and IHD, paroxetine was not associated with significant changes in heart rate, heart rate variability, blood pressure, or conduction intervals. Both pharmacotropical agents demonstrated improvement in depressive symptoms. Interestingly, paroxetine has also been studied for the treatment of atrial fibrillation due to its effects on vagal tone and ability to inhibit the vasovagal reflex. Although this study was small (9 male patients with paroxysmal atrial fibrillation), response was favorable.
The sertraline antidepressant heart attack trial (SADHAT Trial) concluded that sertraline was both efficacious and safe in patients with major depression after a MI. In the follow-up study to SADHAT, known as sertraline antidepressant heart attack randomized trial (SADHART), which randomly assigned 369 patients with MDD and either acute MI or unstable angina to either placebo or sertraline, sertraline was again found to show no significant difference in ejection fraction or any other cardiovascular measures. In subgroups with recurrent depressive episodes, sertraline was found to be significantly superior to placebo on both the Clinical Global Impression Scale (CGI) and Hamilton Rating Scale for Depression (HAM-D) measures. Results of the Sertraline Against Depression and Heart Disease (SADHART) in chronic heart failure trial demonstrated that sertraline was safe to use in patients with heart failure, although it did not demonstrate a greater reduction in depressive symptoms. However, the authors point out that the mean dose of sertraline may have been insufficient to demonstrate efficacy, and that the level of depression in the population being study may not have been severe enough to respond to sertraline therapy.
The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy trial found that when compared to placebo, citalopram was superior in reducing 12-week HAM-D scores. There were no differences between citalopram and placebo when considering blood pressure changes or electrocardiography (ECG) measures, including QTc intervals. However, Beach et al. demonstrated that citalopram increased the QTc interval by 10.58 ms significantly greater than increases found in sertraline, paroxetine, or fluvoxamine. This ultimately prompted the Food and Drug Administration (FDA) to issue a warning in 2011 regarding the use of citalopram above 40 mg/day due to the potential changes in the electrical activity of the heart. Still, newer research done by Zivin et al. published in 2013 did not identify an elevated risk of ventricular arrhythmias associated with citalopram doses >40 mg/day and in fact demonstrated that higher doses were associated with fewer adverse outcomes. As such, the FDA warning may warrant revision.
The study (depression in patients with coronary artery disease [CAD]) evaluated the prevention of post-ACS depression, and ultimately showed that depression was prevented in post-ACS patients taking the medication. This study did not demonstrate any increase in QTc prolongation. However, using data secured from electronic health records, Castro et al. found escitalopram to prolong the QT interval in a dose-dependent manner. Therefore, caution is advised in using either escitalopram or citalopram in patients with increased risk of prolonged QT intervals.
To summarize, SSRIs as a class have a favorable side effect profile, are relatively safe in patients with CVD, and are efficacious in treating depression. Consequently, SSRIs should be considered first line if a pharmacological treatment for depression in a patient with CVD is warranted.
Selective norepinephrine reuptake inhibitors
There is limited evidence regarding the safety of selective norepinephrine reuptake inhibitors (SNRIs) in patients with CVD. Much must be extrapolated from studies done with healthy patients. Venlafaxine has been associated with statistically significant dose-dependent increases in SBP and DBP and thus an increased risk for clinical HTN, particularly in patients with anxiety disorders. Venlafaxine doses >200 mg daily seem to confer the highest incidence of clinically significant blood pressure changes, with increases in supine DBP seen in 5.5% of patients. A small study (59 patients) done by Johnson et al. with venlafaxine extended-release (mean dose 195.5 mg daily) demonstrated no pulse or EKG changes, but induction of HTN in 36% of patients who were normotensive at baseline. Rare QT prolongation has been reported with venlafaxine at therapeutic doses and in overdose., Newer SNRIs, such as duloxetine and desvelafaxine, have very limited data but, at this point, do not demonstrate significant QT prolongation., In addition, Wernicke et al. found that while patients who were started on duloxetine did have blood pressure changes early in treatment, these changes ultimately stabilized over a year of taking it. Hypertensive crisis has been reported in <1% of patients taking duloxetine and ≤1% in patients taking desvenlafaxine. SNRIs, such as SSRIs, have antiplatelet properties. As mentioned above, this is thought to be mediated by blocking platelet 5-HT2A receptors. Duloxetine has a high affinity for this serotonin transporter, but unlike the SSRIs with a similar affinity, duloxetine use in post-MI patients did not confer reduced odds of MI. However, it might be prudent to avoid using duloxetine in patients who are also taking antiplatelet agents in addition to an anticoagulant, and instead chose an agent with lower serotonin affinity. Venlafaxine is classified as being in the “moderate affinity group” by Castro et al.
While not first line, SNRIs seem to offer a relatively safe alternative in patients with CVD, provided blood pressure is closely monitored, drug interactions are avoided, and titration occurs slowly.
Evidence exists supporting the use of other classes of antidepressants in patients with comorbid depression and CVD, although SSRIs still appear to be the first-line recommendation by most. While there is limited information regarding some of the newer agents, a fair amount of research has been done on the use of bupropion and mirtazapine in the CVD population.
Given the frequent comorbidity of tobacco use with depression and CVD, the ability of bupropion to target nicotine withdrawal makes it a medication that may be particularly helpful in this population. Rigotti et al. demonstrated that bupropion is well tolerated in patients hospitalized with acute CVD. In addition, Castro et al. classify bupropion as having a “low affinity” for the serotonin transporter, which, as discussed above, is associated with lower risk of GI bleeds. As such, if a CVD patient needs to be on an antiplatelet agent, bupropion may be the safer option compared to an SSRI. However, the use of bupropion is not without risk in the CVD population. Bupropion was associated with a statistically significant increase in supine blood pressure in patients with preexisting left ventricular impairment. This mirrors findings in healthy controls. Bupropion has also been linked to increased episodes of angina, further limiting its use in patients who suffer from CVD. However, the authors noted that chest pain was more common in patients who were titrated to higher doses quickly, and in one patient, resolved once the dose was lowered.
Mirtazapine use in patients with CVD has also been studied. The MI and Depression Intervention (MIND-IT) trial evaluated the safety and efficacy of mirtazapine in patients with a post-MI depressive disorder. Investigators demonstrated a statistically significant difference favoring mirtazapine to placebo on the HAM-D, beck depression inventory, and CGI scales. No changes in ECG variables were noted, although weight increased by 1.7 kg in the first 8 weeks of mirtazapine use. As such, mirtazapine use should be avoided in patients with CVD and obesity, and weight should be closely monitored in patients without underlying obesity. Mirtazapine is also classified as “low affinity” for the serotonin transporter, which, as discussed above, results in less bleeding potential  and may be a better option for patients with CVD who also need to be on anticoagulants/antiplatelet agents. Finally, if combined with clonidine, mirtazapine use could result in hypertensive urgency. In a case report published by Abo-Zena et al., a patient previously stabilized on clonidine began to experience episodes of hypertensive urgency after mirtazapine was added to his daily drug regimen. The authors hypothesize that this is secondary to the competing actions of the two drugs. Mirtazapine antagonizes central alpha-2 inhibitory receptors whereas clonidine's actions are stimulatory.
Although not first line due to their less favorable safety profile compared to SSRIs, mirtazapine and bupropion are relatively safe and effective medications for patients suffering from both depression and CVD provided careful attention is paid to blood pressure, drug–drug interactions, and weight gain.
| Integrative Approaches to the Treatment of Depressive Disorder|| |
It has been known in psychiatry that the remission rate of depression treated with the first round antidepressants is only one-third, prompting exploration into other factors that may be involved in the pathogenesis of depression. Current understanding of MDD pathophysiology is based on a multifactorial approach, including micronutrient deficiency, monoamine impairment, inflammatory or cytokine alterations, and gut–brain axis dysregulation. By targeting an array of these key neurobiological pathways through either specific diet changes or other dietary supplements, one is better able to address the multifaceted origin of depression. The following sections discuss the use of integrative/supplemental medications to address symptoms of depression, with particular focus on safety and tolerability evidence that exists in the CVD population.
S-Adenosyl methionine (SAMe) is an endogenous sulfur-containing compound that plays a critical role in the one-carbon cycle responsible for the methylation of neurotransmitters that regulate mood., Patients with CAD have been found to have lower level of SAMe, with SAMe supplementation often recommended to patients with CAD. SAMe has been reported safe and effective for the treatment of depression, either as monotherapy for mild and moderate depression or augmentation for treatment-resistant depression not responsive to an SSRI.,,,,, The efficacy and safety of using SAMe administered orally or intramuscularly was comparable to that of imipramine administered orally with fewer side effects and an earlier onset of action. Although the authors are unaware of any studies specific to the use of SAMe as a treatment for depression in patients with CVD, extrapolation from healthy controls would indicate it is a viable option for this patient population.
Folate, Vitamin B6, and Vitamin B 12
A deficiency of vitamin B6, B12, or folate will lead to increased blood homocysteine levels, which is a key risk factor in the pathogenesis of atherosclerosis. Hyperhomocysteinemia, which has been reported in patients with MDD,,, can result in endothelial cell injury, inflammation of the blood vessels and subsequent atherogenesis, and ischemic injury such as CAD or stroke. It has been shown that folic acid treatment for hyperhomocysteinemia reduced the levels of both homocysteine and pro-inflammatory cytokines. Low levels of folic acid may be associated with depressive symptoms and poor response to antidepressants. Daily supplementation with 500 mg of folic acid in a study of 127 patients with depression resulted in a significant enhancement of fluoxetine. Similarly, in 213 outpatients with MDD, those with low folate levels at baseline showed a poorer response to fluoxetine. Therefore, one imagines that treatment of hyperhomocysteinemia with folic acid may be beneficial to patients with depression and CVD, especially those on concomitant antidepressants.
Omega-3 fatty acids
Numerous researchers have identified reduced omega-3 to Omega-6 fatty acid (Omega-6) FA ratios in patients with CAD and depressive symptoms.,, In patients with recent acute coronary symptoms, Frasure et al. found that patients with MDD and ACS had significantly lower plasma levels of omega-3 polyunsaturated fatty acids, particularly DHA, compared to CVD patients without MDD. Chang et al. also found that patients with CVD and comorbid depression had significantly lower omega-3 polyunsaturated fatty acid levels compared to CVD patients without depression. Supplementation with omega-3 FA in patients with CVD and depression, either as monotherapy or in combination with an antidepressant, appears to be a promising treatment option. However, care must be taken given the theoretical risk of increased bleeding when omega-3 FA supplementation is utilized, particularly when it is combined with other antiplatelet medications such as aspirin or clopidogrel. Interestingly, however, several studies have demonstrated little to no risk of increased bleeding, even when combined with antiplatelet agents.,, Specifically, Watson et al. showed that even high doses of omega-3 FA (up to 4 g daily) did not increase the risk of bleeding when taken with aspirin or clopidogrel. As such, providers should be cognizant of a possible increased bleeding risk when supplementing with omega-3 FA, but it does not appear to be a contraindication to their use. Freeman et al., “Because psychiatric illnesses and CVD may be comorbid, the omega-3 FA Subcommittee of the American Psychiatry Association supports the American Heart Association's guidelines regarding fish consumption, and further recommends that patients with mood, impulse control, or psychotic disorders consume ≥1 g/d of combined EPA and DHA.”
Cholesterol, statin, and CoQ 10
For years, cholesterol has been regarded as the “culprit” associated with cardiac and cerebral vascular diseases, often prompting aggressive treatment of hypercholesterolemia. However, Shrivastava et al. found that chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin1A receptors and may suppress some cytokine (interferon-r, interleukin [IL-2], and IL-12) expression through immunomodulation, especially by more lipophilic statins that readily penetrate the blood–brain barrier. Decreased cytokine expression in the brain further results in lowing of tryptophan (a precursor of serotonin) availability and decreased serotonin synthesis.
The current clinical guideline for cardiologists and primary care physicians are as follows: check the cholesterol level in patients with severe depression or those who do not respond or only partially respond to antidepressants; monitor and address the depressive and other psychiatric symptoms that may be related to the use of certain cholesterol lowing drugs; adjust the serum total cholesterol level not lower than 160 mg/dl while maintaining a desirable balance between HDL and LDL cholesterol; if necessary, substitute the lipophilic statin with a nonlipophilic statin.,
Coenzyme Q10, an intracellular lipid-soluble antioxidant, is a key component of the mitochondrial respiratory chain for adenosine triphosphate synthesis. It is significantly associated with a reduced the risk of CAD. Statins block the synthetic pathway shared by CoQ10 and cholesterol. Therefore, everyone on a statin should be treated with CoQ10. CoQ10 of 100 mg/day should be given to individuals who are over 50, use statins, or on CoQ10 reducing medications (i.e., metformin, beta blockers, some anti-HTN medication).,,,
5-HTP has been found to be effective as an antidepressant compared to placebo, at least as effective as fluvoxamine, and more effective than tricyclic drugs., 5-HTP also showed positive augmentation effects when adjunct with phenelzine sulfate, clomipramine, tranylcypromine, and fluoxetine. In addition to decreasing the symptoms of depression, 5-HTP also has a number of other advantages for people with CAD. It may help relieve anxiety, improve sleep, and suppress the appetite. Theoretically, 5-HTP has risk of serotonin syndrome if combined with other serotonergic agents but no cases have been reported. In general, it is considered safe with monitoring.
St John's wort
St. John's wort (Hypericum perforatum) is an herb that has been used for centuries for medical purposes. Likely via acting at GABA, NMDA, dopamine, and serotonin receptors, St. John's wort has been reported to be effective in treating mild to moderate (but not severe) depression., Its efficacy is comparable to SSRI or TCA in these cases, but great care must be taken to be mindful of possible drug–drug interactions through cytochrome P450 interactions. Possible drug–drug interactions of particular importance in patients with CVD include St. John's wort's ability to decrease the potency of birth control pills, cyclosporine, digoxin, warfarin, protease inhibitors, or theophylline while increasing the potency of MAOIs, SSRIs, alcohol, triptans, or certain narcotics. Also of note, St. John's wort does have anti-inflammatory effects which may be beneficial to patients suffering from comorbid CVD and depression. However, further research is needed to fully understand its safety and effectiveness in this population.
Saffron, a spice derived from the flower of Crocus sativus, has many active constituents that likely contribute to its mechanism of action. Mechanisms that may have relevance to treatment of depression include its antioxidant, serotonergic, anti-inflammatory, and neuroprotective effects. Several clinical trials have showed saffron to have efficacy in treating mild and moderate depression similar to fluoxetine and imipramine.,, No serious side effects were reported from saffron studies. Saffron has also been shown to have cardioprotective properties, thought to be mainly due to its crocin constituent, via scavenging of free radicals, antioxidant effects, and hypotensive effects. One small clinical trial comparing saffron to fluoxetine in depressed patients with a prior history of postpercutaneous coronary intervention showed similar efficacy. Given the antidepressant and cardioprotective effects of saffron in the context of a better side effect profile, its use as a treatment for patients suffering from comorbid depression and CVD is promising.
| Discussion|| |
Both CVD and depression are highly prevalent diseases, cause a significant decrease in quality of life for the patients, and impose a significant economic burden on society. Depression is an independent risk factor leading to a cardiac event, which has been shown in patients with or without known CAD. Depression can exacerbate CVD, and CVD can exacerbate depression. Thus, effectively treating depression enhances heart disease treatment. However, the current limitation is that patients with CVD often do not receive effective depression treatment. Several possible explanations may account for this. First, internists/cardiologists may not understand or recognize the strong link between CVD and depression, and in turn give preferential attention to cardiovascular complaints over those pertaining to mental illness. Second, patients may be reluctant to admit to symptoms of a mental illness due to the negative stigma associated with these diseases. Moreover, even when patients are willing to accept treatment, they may still have insufficient access to mental health specialists.
This article reviewed the current psychopharmacological and integrative approaches in treating the depression in patients with CAD. Given the clinical complexity of this special population and the limited effectiveness of the antidepressants, the writers proposed the integration of the traditional antidepressants with supplements to effectively treat the CAD patients with depression. Since poor diet is commonly observed in patients with both depression and CVD, we recommend the followings: (1) supplementing patients' diets with a multivitamin, folate, and omega-3 FA. The dose of the Omega-3 FA should be at least 1 g/day but no more than 4 g/day. (2) Serum total cholesterol level should closely be monitored in patients who are on statins, with careful attention paid to keeping total cholesterol above 160 mg/dl to prevent lack of response or inadequate response to antidepressants. (3) Use the nonlipophilic statins if possible. (4) CoQ10 should be administered to all patients who are over 50, use stains or on CoQ10 reducing medications. However, pharmacological treatment of depression in this patient population must be done with care, paying particular attention to potential cardiac side effects and drug–drug interactions. For antidepressant options, SSRIs remain the first line due to their tolerability and relative absence of significant cardiovascular side effects, though SNRIs, mirtazapine, bupropion, and less frequently TCAs may be appropriate in certain populations when carefully monitored. Providers should also consider the nutraceutical formulations as alternatives if antidepressants are not effective or not suitable to use due to their adverse cardiac effects.
| Conclusion and Future Direction|| |
To summarize, treatment of depression in patients with comorbid CVD is imperative for both mental and physical health, with numerous options available. The use of supplements to treat depression in patients with CVD should not be overlooked, as there are good data to suggest efficacy, improved tolerability, and possible cardioprotective effects when these medications are used either in place of or in conjunction with traditional antidepressants. The authors believe that the key to effectively treating depression in patients with CVD is to increase the awareness of the mind and heart connection. Further research is warranted to address how to best help this patient population, with particular attention paid to effective ways of facilitating interdisciplinary cooperation between specialties as a mean of treating the whole person. In addition, there is limited research regarding the use of supplements in the CVD population. Several supplements show great promise in treating depression in patients without comorbid CVD. Expanding this research to include patients with CVD could be hugely beneficial to a population that is in great need, particularly because patients may find supplement or nutraceutical formulation use are less stigmatizing compared to traditional antidepressants.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Penninx BW. Depression and cardiovascular disease: Epidemiological evidence on their linking mechanisms. Neurosci Biobehav Rev 2017;74(Pt B):277-86.
Kuehl LK, Muhtz C, Hinkelmann K, Dettenborn L, Wingenfeld K, Spitzer C, et al.
Association between major depression and cardiovascular risk: The role of antidepressant medication. Psychopharmacology (Berl) 2016;233:3289-95.
Dhar AK, Barton DA. Depression and the link with cardiovascular disease. Front Psychiatry 2016;7:33.
Mavrides N, Nemeroff C. Treatment of depression in cardiovascular disease. Depress Anxiety 2013;30:328-41.
Stewart RA, North FM, West TM, Sharples KJ, Simes RJ, Colquhoun DM, et al.
Depression and cardiovascular morbidity and mortality: Cause or consequence? Eur Heart J 2003;24:2027-37.
Myers V, Gerber Y, Benyamini Y, Goldbourt U, Drory Y. Post-myocardial infarction depression: Increased hospital admissions and reduced adoption of secondary prevention measures – A longitudinal study. J Psychosom Res 2012;72:5-10.
Chung ML, Dekker RL, Lennie TA, Moser DK. Antidepressants do not improve event-free survival in patients with heart failure when depressive symptoms remain. Heart Lung 2013;42:85-91.
Taylor CB, Youngblood ME, Catellier D, Veith RC, Carney RM, Burg MM, et al.
Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005;62:792-8.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al.
Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006;163:1905-17.
Pariante CM. Neuroscience, mental health and the immune system: Overcoming the brain-mind-body trichotomy. Epidemiol Psychiatr Sci 2016;25:101-5.
Blumenthal JA, Jiang W, Babyak MA, Krantz DS, Frid DJ, Coleman RE, et al.
Stress management and exercise training in cardiac patients with myocardial ischemia. Effects on prognosis and evaluation of mechanisms. Arch Intern Med 1997;157:2213-23.
Milani RV, Lavie CJ. Impact of cardiac rehabilitation on depression and its associated mortality. Am J Med 2007;120:799-806.
Kellner R. A symptom questionnaire. J Clin Psychiatry 1987;48:268-74.
Linden W, Stossel C, Maurice J. Psychosocial interventions for patients with coronary artery disease: A meta-analysis. Arch Intern Med 1996;156:745-52.
Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interventions for depression in patients with coronary artery disease. Cochrane Database Syst Rev 2011;(9):CD008012. doi: 10.1002/14651858.CD008012.pub3.
Rees K, Bennett P, West R, Davey SG, Ebrahim S. Psychological interventions for coronary heart disease. Cochrane Database Syst Rev 2004;(2):CD002902.
Robinson DS, Amsterdam JD. The selegiline transdermal system in major depressive disorder: A systematic review of safety and tolerability. J Affect Disord 2008;105:15-23.
Teply RM, Packard KA, White ND, Hilleman DE, DiNicolantonio JJ. Treatment of depression in patients with concomitant cardiac disease. Prog Cardiovasc Dis 2016;58:514-28.
Shores MM, Pascualy M, Veith RC. Major depression and heart disease: Treatment trials. Semin Clin Neuropsychiatry 1998;3:87-101.
Glassman AH, Johnson LL, Giardina EG, Walsh BT, Roose SP, Cooper TB, et al.
The use of imipramine in depressed patients with congestive heart failure. JAMA 1983;250:1997-2001.
Bigger JT, Giardina EG, Perel JM, Kantor SJ, Glassman AH. Cardiac antiarrhythmic effect of imipramine hydrochloride. N Engl J Med 1977;296:206-8.
Roose SP, Miyazaki M. Pharmacologic treatment of depression in patients with heart disease. Psychosom Med 2005;67 Suppl 1:S54-7.
Glassman AH, Preud'homme XA. Review of the cardiovascular effects of heterocyclic antidepressants. J Clin Psychiatry 1993;54 Suppl:16-22.
Alvarez W Jr., Pickworth KK. Safety of antidepressant drugs in the patient with cardiac disease: A review of the literature. Pharmacotherapy 2003;23:754-71.
Roose SP, Glassman AH, Giardina EG, Walsh BT, Woodring S, Bigger JT. Tricyclic antidepressants in depressed patients with cardiac conduction disease. Arch Gen Psychiatry 1987;44:273-5.
Shrivastava RK, Cohn C, Crowder J, Davidson J, Dunner D, Feighner J, et al.
Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. J Clin Psychopharmacol 1994;14:322-9.
Roose SP, Laghrissi-Thode F, Kennedy JS, Nelson JC, Bigger JT Jr., Pollock BG, et al.
Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998;279:287-1.
Roose SP, Glassman AH, Attia E, Woodring S, Giardina EG, Bigger JT Jr. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998;155:660-5.
Lexi-Comp. Lexi-Comp Online. Vol. 44236. Hudson, Ohio: Lexi-Comp; 2014.
Regan KL. Depression treatment with selective serotonin reuptake inhibitors for the postacute coronary syndrome population: A literature review. J Cardiovasc Nurs 2008;23:489-96.
Maurer-Spurej E. Serotonin reuptake inhibitors and cardiovascular diseases: A platelet connection. Cell Mol Life Sci 2005;62:159-70.
Castro VM, Gallagher PJ, Clements CC, Murphy SN, Gainer VS, Fava M, et al.
Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants. BMJ Open 2012;2:e000544.
Pizzi C, Rutjes AW, Costa GM, Fontana F, Mezzetti A, Manzoli L. Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. Am J Cardiol 2011;107:972-9.
Benfield P, Ward A. Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1986;32:313-34.
Dent LA, Orrock MW. Warfarin-fluoxetine and diazepam-fluoxetine interaction. Pharmacotherapy 1997;17:170-2.
Drake WM, Gordon GD. Heart block in a patient on propranolol and fluoxetine. Lancet 1994;343:425-6.
Walley T, Pirmohamed M, Proudlove C, Maxwell D. Interaction of metoprolol and fluoxetine. Lancet 1993;341:967-8.
Roose SP, Glassman AH, Giardina EG, Johnson LL, Walsh BT, Woodring S, et al.
Nortriptyline in depressed patients with left ventricular impairment. JAMA 1986;256:3253-7.
Strik JJ, Honig A, Lousberg R, Lousberg AH, Cheriex EC, Tuynman-Qua HG, et al.
Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: Findings from a double-blind, placebo-controlled trial. Psychosom Med 2000;62:783-9.
Shirayama T, Sakamoto T, Sakatani T, Mani H, Yamamoto T, Matsubara H. Usefulness of paroxetine in depressed men with paroxysmal atrial fibrillation. Am J Cardiol 2006;97:1749-51.
Shapiro PA, Lespérance F, Frasure-Smith N, O'Connor CM, Baker B, Jiang JW, et al.
An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial. Am Heart J 1999;137:1100-6.
Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT Jr., et al.
Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288:701-9.
O'Connor CM, Jiang W, Kuchibhatla M, Silva SG, Cuffe MS, Callwood DD, et al.
Safety and efficacy of sertraline for depression in patients with heart failure: Results of the SADHART-CHF (Sertraline against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol 2010;56:692-9.
Lespérance F, Frasure-Smith N, Koszycki D, Laliberté MA, van Zyl LT, Baker B, et al.
Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007;297:367-79.
Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA, et al.
Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry 2014;75:e441-9.
Zivin K, Pfeiffer PN, Bohnert AS, Ganoczy D, Blow FC, Nallamothu BK, et al.
Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry 2013;170:642-50.
Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, et al.
QT interval and antidepressant use: A cross sectional study of electronic health records. BMJ 2013;346:f288.
Feighner JP. Cardiovascular safety in depressed patients: Focus on venlafaxine. J Clin Psychiatry 1995;56:574-9.
Johnson EM, Whyte E, Mulsant BH, Pollock BG, Weber E, Begley AE, et al.
Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiatry 2006;14:796-802.
Venlafaxine: More dangerous than most “selective” serotonergic antidepressants. Prescrire Int 2016;25:96-9.
Jasiak NM, Bostwick JR. Risk of QT/QTc prolongation among newer non-SSRI antidepressants. Ann Pharmacother 2014;48:1620-8.
Wernicke J, Lledó A, Raskin J, Kajdasz DK, Wang F. An evaluation of the cardiovascular safety profile of duloxetine: Findings from 42 placebo-controlled studies. Drug Saf 2007;30:437-55.
Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003;108:32-6.
Rigotti NA, Thorndike AN, Regan S, McKool K, Pasternak RC, Chang Y, et al.
Bupropion for smokers hospitalized with acute cardiovascular disease. Am J Med 2006;119:1080-7.
Kiev A, Masco HL, Wenger TL, Johnston JA, Batey SR, Holloman LC. The cardiovascular effects of bupropion and nortriptyline in depressed outpatients. Ann Clin Psychiatry 1994;6:107-15.
de Graaf L, Diemont WL. Chest pain during use of bupropion as an aid in smoking cessation. Br J Clin Pharmacol 2003;56:451-2.
Honig A, Kuyper AM, Schene AH, van Melle JP, de Jonge P, Tulner DM, et al.
Treatment of post-myocardial infarction depressive disorder: A randomized, placebo-controlled trial with mirtazapine. Psychosom Med 2007;69:606-13.
Abo-Zena RA, Bobek MB, Dweik RA. Hypertensive urgency induced by an interaction of mirtazapine and clonidine. Pharmacotherapy 2000;20:476-8.
Williams AL, Girard C, Jui D, Sabina A, Katz DL. S-adenosylmethionine (SAMe) as treatment for depression: A systematic review. Clin Invest Med 2005;28:132-9.
Baek JH, Bernstein EE, Nierenberg AA. One-carbon metabolism and bipolar disorder. Aust N
Z J Psychiatry 2013;47:1013-8.
Loehrer FM, Angst CP, Haefeli WE, Jordan PP, Ritz R, Fowler B. Low whole-blood S-adenosylmethionine and correlation between 5-methyltetrahydrofolate and homocysteine in coronary artery disease. Arterioscler Thromb Vasc Biol 1996;16:727-33.
Papakostas GI. Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry 2009;70 Suppl 5:18-22.
Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: A randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147:591-5.
Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: A review of the evidence. Am J Clin Nutr 2002;76:1158S-61S.
Sarris J, Papakostas GI, Vitolo O, Fava M, Mischoulon D. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: Efficacy and effects of histamine and carnitine as moderators of response. J Affect Disord 2014;164:76-81.
Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double-blind, randomized clinical trial. Am J Psychiatry 2010;167:942-8.
Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, Baer L, et al.
A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. J Clin Psychiatry 2014;75:370-6.
Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: Comparison with imipramine in 2 multicenter studies. Am J Clin Nutr 2002;76:1172S-6S.
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57.
Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-32.
Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: A randomised, placebo controlled trial. J Affect Disord 2000;60:121-30.
Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T. Folate, Vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997;154:426-8.
De Bree A, Verschuren WM, Kromhout D, Kluijtmans LA, Blom HJ. Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol Rev 2002;54:599-618.
Wang G, Dai J, Mao J, Zeng X, Yang X, Wang X. Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia. Atherosclerosis 2005;179:395-402.
Alpert JE, Mischoulon D, Nierenberg AA, Fava M. Nutrition and depression: Focus on folate. Nutrition 2000;16:544-6.
Mazereeuw G, Herrmann N, Ma DW, Hillyer LM, Oh PI, Lanctôt KL. Omega-3/omega-6 fatty acid ratios in different phospholipid classes and depressive symptoms in coronary artery disease patients. Brain Behav Immun 2016;53:54-8.
Frasure-Smith N, Lespérance F, Julien P. Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol Psychiatry 2004;55:891-6.
Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol 2007;99:35C-43C.
Chang JP, Chang SS, Yang HT, Palani M, Chen CP, Su KP. Polyunsaturated fatty acids (PUFAs) levels in patients with cardiovascular diseases (CVDs) with and without depression. Brain Behav Immun 2015;44:28-31.
Watson PD, Joy PS, Nkonde C, Hessen SE, Karalis DG. Comparison of bleeding complications with omega-3 fatty acids + aspirin + clopidogrel – versus – aspirin + clopidogrel in patients with cardiovascular disease. Am J Cardiol 2009;104:1052-4.
Harris WS. Expert opinion: Omega-3 fatty acids and bleeding-cause for concern? Am J Cardiol 2007;99:44C-6C.
Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M, et al.
Omega-3 fatty acids: Evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006;67:1954-67.
Shrivastava S, Pucadyil TJ, Paila YD, Ganguly S, Chattopadhyay A. Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin(1A) receptors. Biochemistry 2010;49:5426-35.
Maes M, Smith R, Christophe A, Vandoolaeghe E, Van Gastel A, Neels H, et al.
Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: Relationship with immune-inflammatory markers. Acta Psychiatr Scand 1997;95:212-21.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
Lee BJ, Lin YC, Huang YC, Ko YW, Hsia S, Lin PT. The relationship between coenzyme Q10, oxidative stress, and antioxidant enzymes activities and coronary artery disease. ScientificWorldJournal 2012;2012:792756.
Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, et al.
Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A 1990;87:8931-4.
Kishi T, Watanabe T, Folkers K. Bioenergetics in clinical medicine XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors. Res Commun Chem Pathol Pharmacol 1977;17:157-64.
Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al.
Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and Vitamin B12 in type 2 diabetes mellitus: A randomized, placebo-controlled trial. J Intern Med 2003;254:455-63.
Saha SP, Whayne TF Jr. Coenzyme Q-10 in human health: Supporting evidence? South Med J 2016;109:17-21.
Shaw K, Turner J, Del Mar C. Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis. Aust N
Z J Psychiatry 2002;36:488-91.
van Praag HM, van den Burg W, Bos ER, Dols LC. 5-hydroxytryptophan in combination with clomipramine in “therapy-resistant” depressions. Psychopharmacologia 1974;38:267-9.
Nardini M, De Stefano R, Iannuccelli M, Borghesi R, Battistini N. Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. Int J Clin Pharmacol Res 1983;3:239-50.
Takahashi S, Kondo H, Kato N. Effect of l-5-hydroxytryptophan on brain monoamine metabolism and evaluation of its clinical effect in depressed patients. J Psychiatr Res 1975;12:177-87.
Kahn RS, Westenberg HG. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord 1985;8:197-200.
Ursin R. The effects of 5-hydroxytryptophan and L-tryptophan on wakefulness and sleep patterns in the cat. Brain Res 1976;106:105-15.
Blundell J. Pharmacological approaches to appetite suppression. Trends Pharmacol Sci 1991;12:147-57.
Linde K. St. John's Wort for depression – Development of a Cochrane review from 1993 to 1996. Z Evid Fortbild Qual Gesundhwes 2008;102:487-92.
Röder C, Schaefer M, Leucht S. Meta-analysis of effectiveness and tolerability of treatment of mild to moderate depression with St. John's Wort. Fortschr Neurol Psychiatr 2004;72:330-43.
Clauson KA, Santamarina ML, Rutledge JC. Clinically relevant safety issues associated with St. John's Wort product labels. BMC Complement Altern Med 2008;8:42.
Saller R, Rostock M. Multimorbidity and multi-target-therapy with herbal drugs. Praxis (Bern 1994) 2012;101:1637-42.
Lopresti AL, Drummond PD. Saffron (Crocus sativus
) for depression: A systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol 2014;29:517-27.
Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic extract of Crocus sativus
L. versus fluoxetine in the treatment of mild to moderate depression: A double-blind, randomized pilot trial. J Ethnopharmacol 2005;97:281-4.
Akhondzadeh S, Kashani L, Fotouhi A, Jarvandi S, Mobaseri M, Moin M, et al.
Comparison of Lavandula angustifolia
Mill. tincture and imipramine in the treatment of mild to moderate depression: A double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:123-7.
Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F. Comparison of Crocus sativus
L. and imipramine in the treatment of mild to moderate depression: A pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med 2004;4:12.
Shahmansouri N, Farokhnia M, Abbasi SH, Kassaian SE, Noorbala Tafti AA, Gougol A, et al.
A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus
L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients. J Affect Disord 2014;155:216-22.
Modaghegh MH, Shahabian M, Esmaeili HA, Rajbai O, Hosseinzadeh H. Safety evaluation of saffron (Crocus sativus
) tablets in healthy volunteers. Phytomedicine 2008;15:1032-7.