Depression - Saffron A Spicy Solution

Saffron, a well known spice used to give a unique flavor and a vivid yellow color to many dishes has been used for centuries in traditional medical systems to treat depression and other illnesses. Recently a number of clinical trials have shown that this spice is as effective as Fluoxetine (Prozac) and imipramine in the treatment of mild to moderate depression.

The spice saffron is a yellow powder derived from the stigmata (styles) of the flowering bulb Crocus sativa. It is cultivated on a commercial basis primarily in Iran and to a lesser extent in India, Spain and a few other countries. Prior to the advent of cheaper, synthetic food colorings, saffron was also grown in other European countries including England.

Although several other spices have demonstrated the potential to prevent and treat several neurological diseases saffron is the first to be tested as a treatment of depression in clinical trials.

The recent clinical studies on patients with depression were conducted by doctors at the Tehran University of Medical Sciences. The double-blind, placebo controlled trials compared the effects of 30 mg per day of saffron powder to those of normal doses of two common anti-depressant drugs, fluoxetine and imipramine. In all three clinical trials they found that saffron was at least as effective as these two commonly used anti-depressant drugs in combating mild to moderate depression.

This latest research shows that we have yet another spice that can help with a neurological illness - in this case, depression. Depression affects all age groups but increases in incidence with age. In other words we can include it with other diseases associated with the aging process; such as cardiovascular disease, diabetes, Alzheimer's disease, Parkinson's disease, cancer and others.

There is some scientific evidence that saffron, like many other other spices, may also help to prevent and treat certain cancers. Saffron contains the compound safranal and many antioxidants such as carotenoids and other compounds common to other spices that have been shown to have anti-cancer properties.

Countless studies have shown that spices can help prevent and treat most age related diseases. To a large extent it is those spice-based compounds responsible for their strong colors and flavors that protect us against many of the underlying disease processes common to these conditions.

Humans evolved eating strongly colored, intensely flavored, bitter, sour, "spicy" foods. Therefore it should come as no surprise to us that it is primarily in spices that a vast repository of therapeutic phytonutrients exists to help us combat depression and other neurological and degenerative diseases.

If we add more spices such as saffron to our meals we will not only be happier with the enhanced flavor but the compounds in these tasty additives should also put more zest into our day and help us to avoid a visit to the psychotherapist.

Do Antidepressants Make Some People Drink More?

A number of studies conducted in the 1980s and the early 1990s showed that SSRIs (selective serotonin reuptake inhibitors) such as Prozac led to short term reductions in alcohol consumption in both humans and rats. This led to a lot of enthusiasm and intensive research on the effects of SSRIs on alcohol consumption because some researchers hoped that SSRIs might hold the key to the cure for alcoholism.

However, the research proved that the effects of SSRIs on alcohol consumption are far less simple than they initially appeared. The short term reductions in drinking in human alcoholics lasted no longer than a week and then the subjects were once again drinking just as much as they ever had. Moreover, the research showed that SSRIs may actually worsen drinking in Early Onset Alcohol Abusers and in women.

There is one group, however, which seems definitely to benefit from SSRIs. Patients who have both Alcohol Dependence and severe Major Depressive Disorder show significant improvement both in depression and alcohol consumption when treated with SSRIs. In this article we will take a look at the research which has been done on SSRIs and alcohol consumption in these populations.

In 1995 and 1996 Dr Henry Kranzler MD and his colleagues did a study which suggests that the SSRI Prozac may actually worsen the drinking behavior of Early Onset Alcohol Abusers while having no effect at all on Late Onset Alcohol Abusers. Early Onset Alcohol Abusers are defined as those who begin heavy drinking in early life and who have worse alcohol related consequences. Late Onset Alcohol Abusers are defined as those who begin heavy drinking later in life and have fewer alcohol related problems.

The Kranzler group studied the effects of Prozac on 95 non-depressed patients who were being treated with talk therapy for Alcohol Dependence. Half of these subjects received Prozac and the other half got a placebo. When Kranzler and his colleagues analyzed the group as a whole they found that there was no significant difference in improvement between the placebo group and the group receiving Prozac.

However, they then divided the patients up into two categories: Late Onset Alcohol Abusers and Early Onset Alcohol Abusers. When they reanalyzed the data using these two categories they obtained a very surprising result which was quite contrary to what they expected. They found that Early Onset Alcohol Abusers receiving the Prozac did significantly WORSE than the group receiving the placebo. There was no significant difference between the Late Onset Alcohol Abusers who received Prozac and those who received the placebo.

The Kranzler study strongly suggests that Prozac may actually worsen the drinking of Early Onset Alcohol Abusers who are not receiving any sort of talk therapy for their Alcohol Dependence. All that remains is for someone to do the crucial experiment needed to verify this highly likely conclusion.

In 1995 Dr Claudio Naranjo MD and his colleagues did a study of the effect of the SSRI Celexa on 62 non-depressed problem drinkers who were being taught moderate drinking strategies. 56% of the subjects in the study were male and 44% were female. Half of the subjects in the study got Celexa and the other half got a placebo. The Naranjo group found that women receiving the Celexa did significantly WORSE than women receiving the placebo in moderating their drinking. The men did the same whether they received Celexa or the placebo. This suggests that Celexa may actually INCREASE the drinking of female problem drinkers who are not receiving moderation training or some other form for talk therapy. All that is needed to confirm this is an experiment with drinkers who are receiving Celexa but no talk therapy.

The patients in the studies we have discussed so far did not suffer from severe Major Depressive Disorder. In 1997 Dr Jack Cornelius MD and his colleagues studied the effect of the SSRI Prozac on 51 patients with both severe Major Depressive Disorder and severe Alcohol Dependence. The subjects were 51% male and 49% female. All patients received talk therapy for their Alcohol Dependence. In addition to the talk therapy, 25 patients received Prozac and 26 received a placebo. In this study the patients who received the Prozac showed significantly greater improvements in both depression and in drinking outcomes than did those receiving the placebo. Taken together with the other studies this leads to the conclusion that SSRIs can lead to a reduction in drinking in people with severe Major Depressive Disorder but not in other groups.

In 2007 Dr Kathryn Graham PhD and her colleagues published the results of a massive telephone survey of 14,063 individuals in Canada which asked people about their use of alcohol and antidepressants. This survey showed that depressed men who took antidepressants drank less alcohol on the average than did depressed men who did not take antidepressants. However, depressed women who took antidepressants drank at least as much as did depressed women who did not take antidepressants, if not more.

Like the Naranjo study, this study also suggests that antidepressants affect the drinking behavior of men differently than they do the drinking behavior of women. Since this study did not specifically ask respondents if they were taking an SSRI or another type of antidepressant such as a tricyclic we must be somewhat cautious in what we can conclude from it. It is possible that if the data were limited to SSRIs that the researchers might have seen an increase in the alcohol consumption of women taking the medication. It remains for further research to confirm whether this is actually the case.

The studies to date seem to suggest that SSRIs only lead to reduced alcohol consumption in men who have severe Major Depressive Disorder. SSRIs do not seem to affect the alcohol consumption of most other people either one way or the other. However, the studies also suggest that it is possible that SSRIs might tend to increase alcohol consumption in some individuals--particularly in women and in Early Onset Alcohol Abusers.

Therefore, we would like to suggest that people become pro-active health care consumers. If you drink alcohol and take antidepressant and the antidepressants seem to be causing you to increase your drinking or to drink in a dangerous fashion, then you should talk to your doctor. You may need to switch to a different kind of antidepressant or stop taking antidepressants altogether. Or you may find that quitting drinking is your wisest course.

REFERENCES:
Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius MD, Perel JM, Thase ME, Black A. (1997). Fluoxetine in depressed alcoholics: a double-blind, placebo-controlled trial. Archives of General Psychiatry, 54, 700-5.
Graham, K, Massak, A. (2007). Alcohol consumption and the use of antidepressants. CMAJ. 176(5), 633-7.
Kranzler HR, Burleson JA, Korner P, Del Boca FK, Bohn MJ, Brown J, Liebowitz
N. (1995). Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in
alcoholics. American Journal of Psychiatry, 152, 391-397.
Kranzler HR, Burleson JA, Brown J, Babor TF. (1996). Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics. Alcoholism: Clinical and Experimental Research, 20, 1534-41.
Naranjo CA, Bremner KE, Lanctot KL. (1995). Effects of Citalopram and a brief psycho-social intervention on alcohol intake, dependence and problems. Addiction, 90, 87-99.

Do Antidepressants Make You Suicidal?

During my residency days Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine (Prozac, Sarafem), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and sertraline (Zoloft), were pushed as being better than older drugs like imipramine, since they specifically acted on the serotonin transporter, and therefore didn't have many of the side effects that were said to result from non-specific effects on many neurochemical systems, including dry mouth. Contrary to popular belief, however, the newer generations of antidepressants don't work any better than the old ones, with the possible exception of the dual reuptake inhibitors.

The primary improvement of SSRIs over tricyclics is a questionable decrease in side effects, and the fact that you can't kill yourself by taking an overdose of them. However, drop out rates are not a lot worse with the old drugs and the new drugs, suggesting that new side effects are just as bad as the old ones. In general the sexual dysfunction and jitteriness that come with the SSRIs can be just as bad as the sedation and dry mouth that come with the old ones. The conquering of the market by the SSRIs was mainly a triumph of marketing skills.

The SSRI medications have not been shown to work better than the older tricyclics. In fact, they actually have less efficacy than is commonly believed (DUAG 1990). The Danish Study Group found that the older tricyclic medication clomipramine worked better for severe depression than paroxetine, although it had more side effects. A review from 15 years ago showed that fluoxetine had only modest efficacy over placebo, with over 80% of the improvement accounted for by a placebo effect (Kirsch et al 2002).

A more recent meta analysis from data submitted to the FDA also showed that 80% of the improvement with antidepressants come from the placebo response. When the data of all studies performed on venlafaxine (Effexor), fluoxetine (Prozac), and nefazodone (Serzone), was lumped together, there was only about a 2-point improvement on a 62 item scale (the 21 item Hamilton Depression Scale) above and beyond the placebo response. The response to this was that the effects of antidepressants are modest, even if real, and that it is not ethical to give placebo.

It was also pointed out that the efficacy of SSRIs is greater than other areas of medicine, like the use of statins. Others have argued that SSRIs may not be much better than placebo, but that the relapse rate is much higher on placebo. However, studies following patients who were treated with antidepressants did not show that they did better over the long haul, in fact they may have done worse, even accounting for baseline differences in symptom severity (Moncrieff and Kirsch 2005). There are no studies showing that in the long run people treated with antidepressants are better off. It might be questioned whether a 2 point increase on a 62 item scale that may not be sustainable is a clinically meaningful improvement.

Worry over the efficacy of SSRIs prompted a re-examination of the efficacy of antidepressants in general, and a look at how placebos may work just as well. A meta-analysis showed that there was a highly variable response to placebos, up to 50%, and that the placebo response rate in studies of depression seemed to be growing over the years. In addition, studies in private research firms seemed to be having higher placebo response rates than in universities, suggesting differences in populations, assessments, or inducements for participation.

A more troubling problem is the potential for suicidality associated with SSRIs. The FDA recently added a warning that SSRI antidepressants may increase the risk of suicidal thoughts or suicide. A recent meta-analysis of adults taking SSRIs showed no increase in suicidal thoughts or attempts, while there was a 57% increase in non fatal self harm with SSRIs that was of borderline statistical significance. Another meta-analysis did show a greater than two-fold increase in fatal and non-fatal suicide attempts in patients on SSRI versus placebo, and on SSRI compared to other non-medication treatments. The risk was 5.6 per 1000 patient years (the number of years people take the drug times the number of patients). In other words, if 100 people each took an SSRI for 10 years, about five of them would make a suicide attempt that they wouldn't have done if they weren't on suicide.

There was no difference, however, between SSRIs and the older tricyclic antidepressants, suggesting that all antidepressant medications may carry an increased risk of suicide. Questions about suicidal thinking with antidepressants have been around for years, and occurred with the tricyclics. Some doctors, including my father (who is a retired psychiatrist) offer the explanation that the increase in energy that antidepressants experience often gives the suicidal patient enough stamina to go through with the act. Another disturbing trend that came from this analysis was the change in suicidal thoughts over time. There are 24.5 million visits for depression in the US per year, a 70% increase from 15 years ago. Sixty nine percent of these visits result in a prescription for an antidepressant. The analysis showed that the risk of suicidal thinking and suicide itself has been gradually increasing over the years. It is unclear if this is fueled by an increase in prescribing, primarily by primary care physicians, or other causes.

The latest group of antidepressants has dual reuptake inhibition for serotonin and norepinephrine (SNRIs), and includes venlafaxine (Effexor) and duloxetine (Cymbalta). In general, effexor and duloxetine have shown better treatment response for depression than SSRIs and tricyclics. One study looked at data from a number of randomized, placebo controlled trials of Effexor, tricyclic antidepressants and SSRIs for the treatment of depression. Treatment response was defined as a 50% reduction in symptoms of depression. Forty-four studies with 4033 patients were included.

Overall, venlafaxine had a success rate of 74% that was statistically significantly better than SSRIs, which only had a 61% success rate, and tricyclics, which only had a 58% success rate. The difference in the efficacy of tricyclics and SSRIs was not statistically significant. However, it is worth noting that a larger number of patients dropped out of treatment while on tricyclics because of side effects. Other studies have shown better responses for venlafaxine and duloxetine than tricyclics and SSRIs. Venlafaxine has been associated with a dose dependent increase in blood pressure. Venlafaxine seems to carry the greatest risk of suicidality amongst all of the antidepressants, with a three fold increased risk of attempted or completed suicides.

Review Of SSRIs - Selective Serotonin Reuptake Inhibitors

The most significant class of antidepressants marketed in recent years is the selective serotonin reuptake inhibitors (SSRIs). The six SSRIs available in the United States are citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). The primary uses for the SSRIs include unipolar and bipolar major depression and all of the anxiety disorders. However, controlled trials also support the use of SSRIs in the treatment of other psychiatric disorders including dysthymia, premenstrual dysphoria, bulimia nervosa, obesity, borderline personality disorder, alcoholism, rheumatic pain, and migraine headache.

Among the SSRIs, there are more similarities than differences. Although all SSRI drugs have the same the mechanism of action, each SSRI has a slightly different pharmacological and pharmacokinetic characteristics. This leads to differences among the SSRIs in their half-lives, clinical activity, side effects, and drug interactions. There are differences between SSRIs that could be clinically significant.

The first drug in the SSRI class was Prozac (Fluoxetine), which hit the United States market in 1987. Prozac was FDA approved on December 29, 1987. It is manufactured by Eli Lilly and Company.

Zoloft (Sertraline hydrochloride) was the second SSRI to come to market in the United States, and it was approved by the FDA on December 30, 1991. Zoloft is manufactured by Pfizer Inc.

Paxil (Paroxetine hydrochloride) was the third SSRI to come to market in the United States and was approved by the FDA on December 29, 1992. Paxil is manufactured by GlaxoSmithKline.

Luvox (Fluvoxamine maleate) was the next SSRI FDA approved on December 05, 1994. However, now its marketing status is "Discontinued".

Celexa (Citalopram hydrobromide) was approved by the FDA on July 17, 1998. Celexa is manufactured by Forest Pharmaceuticals, Inc.

Lexapro (Escitalopram oxalate) is the newest and most selective of the SSRIs approved by the FDA on August 14, 2002. Lexapro is manufactured by Forest Pharmaceuticals, Inc. Lexapro is a cleaner, improved version of Celexa.

Mechanism of action

The brain communicates with itself through the use of special chemicals called neurotransmitters, such as serotonin and norepinephrine. Neurotransmitters carry signals from one nerve cell to another. Low levels of serotonin and norepinephrine have not been proven to cause depression but it widely believed that elevation of these chemicals is associated with improvement in mood in depressed people.

All SSRIs have the same general mechanism of action. SSRIs seem to relieve symptoms of depression by blocking the reabsorption (reuptake) of serotonin by certain nerve cells in the brain. This leaves more serotonin available, which enhances neurotransmission (sending of nerve impulses) and improves mood. In due course, the levels of natural serotonin will rise again, and in some instances the SSRI can be reduced and withdrawn.

Approved indications and uses

SSRIs have been primarily used for the treatment of depression and have been studied for several indications outside of depression.

Celexa (Citalopram) is indicated for the treatment of:

• depression

Lexapro (Escitalopram) is indicated for the treatment of:

• major depressive disorder
• generalized anxiety disorder (GAD)

Paxil (Paroxetine) is indicated for the treatment of:

• major depressive disorder
• obsessive compulsive disorder (OCD)
• panic disorder
• social anxiety disorder
• generalized anxiety disorder
• posttraumatic stress disorder (PTSD)

Prozac (Fluoxetine) is indicated for the treatment of:

• major depressive disorder
• obsessive-compulsive disorder
• moderate to severe bulimia nervosa
• panic disorder
• in January 2003, Prozac was approved by the FDA for the treatment of depression and OCD in children and adolescents who are 7 to 17 years of age.

Zoloft (Sertraline) is indicated for the treatment of:

• major depressive disorder
• obsessive-compulsive disorder
• panic disorder
• posttraumatic stress disorder
• premenstrual dysphoric disorder (PMDD) in adults (newest indication)
• social anxiety disorder

Efficacy

Clinical trials comparing an SSRI with another SSRI indicate that drugs in this class are equally efficacious. Each SSRI produces approximately a 60% overall response rate (ie, at least a 50% reduction in symptoms as a result of treatment).

Adverse reactions & side effects

While SSRIs do not appear to differ in overall tolerability, the reported incidences of specific adverse effects vary. Adverse effects that patients experience are usually mild to moderate and do not require dose reductions or discontinuation. SSRIs possess the following adverse effects:

• Nausea. The most coomon side effect accociated with use of SSRIs is nausea. Paroxetine and sertraline have been associated with slightly more cases of nausea.
• Sexual dysfunction. Depression itself may cause sexual dysfunction and all SSRIs have been associated with sexual dysfunction during therapy in men and women. There may be lesser detrimental effect on sexual function by fluoxetine compared to other agents. Citalopram has been associated with loss of libido. Paroxetine appears to cause the highest rate of sexual dysfunction.
• Anticholinergic effects. Paroxetine causes a higher rate of anticholinergic effects, such as dry mouth, constipation, and cognitive disruption, compared with other SSRIs. These effects may be particularly difficult to tolerate for elderly or concomitantly medically ill patients.
• Weight. The SSRIs vary in their effect on the weight. Sertraline is generally associated with a small degree of weight loss in the acute phase of treatment, whereas paroxetine can cause weight gain after long-term treatment. Fluoxetine has the most potent appetite-suppressing effects in the short term and produces a greater degree of weight loss than paroxetine, sertraline, citalopram, or escitalopram.
• Diarrhea. Sertraline and fluoxetine are more frequently associated with diarrhea, paroxetine has a lower incidence.
• Anxiety, agitation, insomnia. Fluoxetine has been associated with highest rate of anxiety and agitation. Escitalopram and paroxatine are less likely to cause insomnia than fluoxetine and sertraline.
• Dry mouth. Citalopram and paroxetine are more likely to cause dry mouth than escitalopram and fluoxetine.
• Drowsiness, fatigue. Paroxetine has been associated with highest rate of drowsiness, somnolence than other SSRIs.
• Headache. Sertraline and fluoxetine are associated with higher level of headache.

In some cases, antidepressants may be associated with worsening symptoms of depression or suicidal thoughts or behavior, particularly early in treatment or when you change your dosage. Be sure to talk to your doctor about any changes in your symptoms. You may need more careful monitoring at the beginning of treatment or upon a change in treatment, or you may need to stop the medication if your symptoms worsen.

Pharmacokinetics

Some of the key differences among SSRIs are due to differences in their pharmacokinetic properties. The only pharmacokinetic parameters shared by all the SSRIs is that they are relatively slowly, but completely, absorbed from the gut. They differ with regard to their protein binding, metabolism, half-lives, whether they have linear or nonlinear pharmacokinetics, whether they have active metabolites.

Half-life

The half-life of a drug is the time required to achieve steady-state plasma concentrations (i.e., to metabolize half the dose and lower blood concentrations by 50%). Half-life can be used to estimate how long it will take to clear a drug from the body after treatment is discontinued.

Fluoxetine is unique because of its long half-life and the long half-life of its active metabolite norfluoxetine. Fluoxetine has a half-life of 4-6 days and its active metabolite, norfluoxetine, has a half-life of 4-16 days. In comparison, citalopram, escitalopram, paroxetine, and sertraline have shorter half-lives in the range of 20-35 hours, and steady-state concentrations (and therapeutic effect) are reached much more rapidly. The long half-life of fluoxetine may blunt the effects of missed doses or treatment discontinuation and makes it easier to discontinue than any of the other SSRIs. On the other hand, fluoxetine requires a much longer washout period than the other SSRIs (several weeks), particularly when switching to monoamine oxidase inhibitors (MAOIs) or TCA.

Antidepressants with relatively short half-lives are desirable for people with multiple comorbidities and complex, multiple-drug regimens because they allow for once-daily dosing. A short half-life enables physicians to switch more rapidly and safely to an alternative antidepressant if treatment fails or if unfavorable drug reactions occur.

Linear and nonlinear pharmacokinetic.

One of the important differences to note among the SSRIs is whether their pharmacokinetic properties are linear or nonlinear.

Citalopram, escitalopram and sertraline show linear and dose-proportional pharmacokinetics. Plasma concentrations of these drugs are proportional to the daily dose administered and, therefore, predictable. In contrast, fluvoxamine, fluoxetine and paroxetine have nonlinear pharmacokinetics. Higher doses may produce much greater increases in plasma drug concentrations than would otherwise be expected. Thus, increasing the dose of paroxetine or fluoxetine can result in disproportionate and unpredictable increases in plasma levels, half-lives, and adverse effects. Titration of fluoxetine and paroxetine doses may therefore be more difficult than with citalopram, escitalopram and sertraline.

Drug Interactions

The interaction between monoamine oxidase inhibitors (MAOIs) and SSRIs is the most important drug interaction limiting SSRI use. This combination may lead to the development of a hyperserotonergic syndrome consisting of excitement, diaphoresis, rigidity, hyperthermia, tachycardia, hypertension, and possibly death. The severity of this interaction necessitates at least 5 week washout when switching a patient from fluoxetine to an MAOI to allow complete elimination of the fluoxetine. At least 14 days should be allowed after stopping citalopram, escitalopram, paroxetine or sertraline before starting an MAOI. This difference in washout time between fluoxetine and citalopram, escitalopram, paroxetine and sertraline when switching from an SSRI to an MAOI is one of the key differences between SSRIs.

Citalopram, escitalopram and sertraline have the lowest potential for drug interactions among the SSRIs. Citalopram should be avoided in patients likely to take overdoses. Sertraline would be preferable for cardiac patients taking beta blockers or type IC antiarrhythmic agents.