Depression and Anxiety: How related?

Dr. Philip Grossi
Wednesday, 27 April 2011

 

 

A frequent chief complaint in my office is anxiety and depression.  Many years ago when I was in training at UCSF, I often noticed when collecting a very detailed history in depressed individuals that they reported a period of anxiety about six to nine months before they became depressed.  Lifetime prevalence of major depressive disorder (MDD) is 16.2% and 28.8% for anxiety (ANX).  Fifty-nine percent of individuals with lifetime MDD were co-morbid for anxiety.  ANX tends to present between the ages of 6 - 20 whereas MDD is spread across adolescence through adulthood.

illustration to depression and anxiety blogUnderstanding the nature of the relationship between ANX and MDD is important because individuals with these co-morbid conditions tend to have greater symptom severity and disability, higher utilization of treatment, and poorer therapeutic response.  The two models researchers have used to explore this relationship are shared etiology (cause) or direct causation. Direct causation states that one disorder causes or makes it more likely to develop the other disorder. My observation that ANX often precedes MDD and foreshadows the course of MDD is supported by many researchers and has led to the speculation that ANX is causally related to MDD.  The shared etiology model postulates that a common group of risk factors lead to the development and expression of both ANX and MDD.  The factors that have been researched include parental mental health problems, non-intact family structure, family dysfunction, socio-economic disadvantage, and peer dysfunction.

Now come A.R.Mathew and colleagues, reporting a study exploring  the relationship between risk factors and the development of ANX and MDD as well as the relationship between the development of ANX on MDD and MDD on the development of ANX.  They studied 1709 adolescents (aged 14-18) from nine high schools in western Oregon.  They made observations at four points with the final point being when the subjects were 30 years of age.  I don't plan to discuss the statistics or methods but simply set out the results.

As expected, they found significant associations between MDD and ANX.  They  were shown to have shared and distinct risk factors.  Low self-esteem was predictive of ANX while attributional style and subthreshold depression were predictive of MDD.  Common predictors of ANX and MDD included female gender, family social support, worry, loneliness, friend social support, and emotional reliance.

The temporal order of onset seems to suggest different etiological models.  ANX remained a significant predictor of MDD even when common risk factors were controlled for.  This extends prior research in that this study controlled for risk factors where prior studies did not.  On the other hand, MDD was not predictive of ANX when common risk factors were included.  Therefore the development of ANX is most likely related to common risk factors.

Some additional findings are:

  • Worry is a risk factor for the development of ANX and also MDD which is consistent with research done by Kendler et.al. showing overlap of MDD and generalized anxiety disorder (GAD).
  • Negative attributional style is predictive of MDD.
  • Poor interpersonal functioning in adolescence with loneliness, emotional reliance, and poor relations with family and peers confers risk for MDD and ANX.
  • Subthreshold depression confers risk for MDD.
  • Substance abuse disorders were predictive of fear type of ANX, i.e. panic disorders

In conclusion, this study supports different etiologic models of ANX-MDD co-morbidity depending on the order of onset.  The path from ANX to MDD is most congruent with the causation model but the path from MDD to later ANX is most congruent with the shared etiology model.

MAOI and Diet

Dr. Philip Grossi
Monday, 04 April 2011

MAOI drugs are widely misunderstood, victimized by outdated and inaccurate information, feared and reviled in much of the professional community.  In spite of this, they are extraordinarily effective when used appropriately, and patients are often pleasantly surprised at the extent of the improvements they obtain with their use. Indeed if the reader goes to AskAPatient.com, they score higher than any other class of antidepressants where a significant number of reviews were posted. This blog is being written to provide information to my patients and thus save me endless repetition and to provide the most current information about tyramine in foods because much of the information in the community is inaccurate. This is meant as a supplement to my office handout.

illustration to MAOI and diet blogFirst and foremost, I want to underline the fact that the reaction to tyramine is a quantitative phenomena, i.e., the degree of reaction is proportional to the amount of tyramine ingested. Portion size is definitely important. The amount of tyramine ingested is a product of the concentration of tyramine in the food times the quantity. Properly stored or fresh meat, poultry, or fish are all right.  Birds or sausages or other meats that hang for periods in delis should be approached with caution.  Smell is something of a guide. The rule of thumb for cheeses is the softer, the older, and the smellier, the higher the tyramine content. Any food whose taste is produced by fermentation should be assessed carefully. Be careful with leftovers. For more information on tyramine restricted foods go to the Grossi's recommended links from the home page of this site. This reaction is the so-called cheese effect or tyramine effect and is characterized by pounding heartbeat, increased blood pressure (usually over 180 mm Hg), slowed heart rate, stiff neck, excruciating headache, tightness in the chest, pallor, diaphoresis, nausea, and confusion.  I have found that in these modern times this is a very infrequent occurrence and death is extremely rare contrary to the reported experience in the 1960s.  When such a reaction does develop, it generally starts within 20 to 30 minutes.  Indeed, if a person on an MAOI ever has a doubt about a food, take a small bite and wait thirty minutes.  If no reaction develops, the food is most likely safe. It is likely that modern food handling and the use of standardized starter cultures for foods, such as cheeses, as well as good refrigeration, all play a role in causing this reaction to be rare these days.

In 2006 A. Azzuro and colleagues ran fourteen tyramine pressors tests on healthy unmedicated, fasting males and found that the amount of tyramine needed to elicit a 30 mm Hg rise in systolic blood pressure was between 400 mgm to 600 mgm.  When tyramine was given with food that more closely simulates daily life, the amount increased by a factor of almost three. When treated with an MAOI, these thresholds decline substantially. To put these numbers into perspective, a high-tyramine meal contains 40 mgm of tyramine. The foods with the highest tyramine content are soy sauce (remember, it is the key ingredient in most marinades and in sauces from Asian countries) and certain cheeses, especially artisanal cheeses such as English Stilton, Cheddar, Parmigiano, Manchego, Compte, Brie, Camembert, Liederkranz, blue cheeses, Emmentaler, Gruyere, and Edam.  Generally, the smellier and the softer and the older, the more the tyramine.  Modern food regulations have led to widespread use of starter cultures which do not contain bacteria with decarboxylase enzymes thus preventing the conversion of tyrosine or phenylalanine into tyramine. It should also be noted that long aging in warehouses is not consistent with modern supermarket food management. Fresh unripened cheeses and yogurts have no tyramine,  e.g., cottage, ricotta and mascarpone.  Be cautious with marmite, sauerkraut, kimchi, and fish sauces, and Spanish dry fermented sausages Chorizo, Fuet, Sobrasada, and Salsichon.  Modern commercial beer and wine can be consumed in moderation though tap beer should be avoided as should any home-made or boutique beer.  If beer has a sediment or is cloudy when swirled, avoid it.  Remember when drinking on an empty stomach the tyramine can be absorbed very quickly and thus a smaller amount is needed to cause some reaction (equivalent to the difference cited above for fasting versus fed study results).  Some Belgian beers, especially Lambic style, have high tyramine content and so should be avoided.

For a more complete discussion and tyramine levels in foods please see  the article Monoamine Oxidase Inhibitors, Dietary Tyramine and Drug Interactions,  an excellent resource maintained and developed by Dr. P. Ken Gillman who has published extensively on this topic.  Many thanks to Dr. Gillman.

MAOIs:Drug Interactions

Dr. Philip Grossi
Sunday, 03 April 2011

Each and every week I receive two or three phone, fax, or email communications from pharmacies questioning my concomitant use of an MAOI with another drug.  Last week I received a phone call from a former patient whom I treated successfully last year and who moved back to Texas because of a job loss.  I had maintained her on tranylcypromine (Parnate) for the last five months while she sought out another psychiatrist in Texas.  She reported last week that she had been unable to find another doctor or psychiatrist who was willing to prescribe the medication for her due to the risks involved in using MAOIs. She stopped taking it and noted that the black dog (she liked Churchill's term for depression) was back. The living purgatory she was experiencing when she first met me had returned.  Such experiences highlight the misunderstanding and  misinformation of a complex subject that is present in the professional community and which is entombed in the Physician's Desk Reference (PDR), textbooks,  drug-checking computer programs, MAOIs' unfortunate 1960's history, and the Food and Drug Administration (FDA) pronouncements..

MAOIs are the oldest class of antidepressants. In the early 1950s, there were some tuberculosis patients being treated with isoniazid and iproniazid who were noted to brighten, show renewed vigor, and were more stimulated.  The drugs' mode of action was discovered to be monoamine oxidase inhibition.  A few years later, phenelzine (Nardil) and tranylcypromine (Parnate) were introduced.  A number of deaths occurred, especially in nursing homes around London, where a snack of English Stilton Cheese and Chianti wine was given in the afternoon. The FDA received about 500 reports of hypertensive crises which resulted in 30 deaths. Consequently, tranylcypromine (Parnate) was withdrawn from the market for about eight months in 1964.  After researchers discovered that their use required a diet low in tyramine (an amino acid), it was reintroduced into the market. 
Thereafter the dietary restrictions were wildly overblown and the drugs were thus rarely prescribed by physicians.  These excessive dietary restrictions were the first of many pieces of flawed information about these drugs. Indeed, most professionals I talk to consider the diet to be the principal danger, when in fact the interaction with other truly contraindicated drugs produce the most dangerous reactions.  This blog is being posted because I want to clarify the misunderstandings about these extraordinarily effective agents and save myself some time by responding to many questions I receive from patients and colleagues.  I do plan to write about the dietary issues in a future blog; this blog will deal with drug interactions only.

 

illustration to MAOIs drug interactions blog

There are two types of dangerous reactions that can occur with an MAOI and certain other drugs.  The first is Serotonin Toxicity or Syndrome (ST or SS).  This is the result of using a serotonin reuptake inhibitor (SRI) and an MAOI concurrently. Serotonin toxicity is the preferred term and should be viewed as a spectrum and not as a Boolean concept. This implies that dosage is a factor as well as the potency of a drug's serotonergic effect.  Hunter's Toxicity Criteria (validated in over 2000 overdoses) for this diagnosis are met if any of the following five criteria obtain :

  • the patient must show spontaneous clonus (involuntary muscle contraction) or
  • tremor and hyperreflexia or
  • ocular clonus and either agitation and diaphoresis or
  • inducible clonus and either agitation or diaphoresis or
  • hypertonia, temperature greater than 38 C and either ocular clonus or inducible clonus.

Severe cases usually manifest higher temperatures. Clonus is the core symptom.  The second dangerous reaction is a sudden rise of blood pressure, usually the result of the indirectly acting sympathomimetic amines (releasers), fenfluramine (Pondimin, no longer available in USA) and MDMA (ecstacy), and pseudophedrine and phenylephrine which are commonly found in OTC cold preparations or tyramine in food.  Read the labels of OTC medications.  If it says do not take if on MAOI, then do not take.  This hypertensive crisis which most patients and professionals focus on is characterized by pounding heartbeat, increased blood pressure (usually over 180 mm Hg), slowed heart rate, stiff neck, excruciating headache, tightness in the chest, pallor, diaphoresis, nausea, and confusion.  This is the so-called cheese effect or tyramine effect and will generally manifest itself within 30 minutes of taking the offending agent.

 

 Avoid concurrent usage of all the following with MAOIs:

 

  • Nuedexa (dextromethorphan and quinidine sulfate)
  • Any two MAOIs contemporaneously
  • Tryptophan
  • MDMA (ecstasy, also known as "X" or "E", popular drug at raves)

Analgesics such as aspirin, tylenol, NSAIDS and the COX2 drugs are safe as are codeine, oxycodone, buprenorphine and morphine.  Benzodiazepines such as clonazepam Klonopin), diazepam (Valium), alprazolam (Xanax), temazepam (Restoril) etc. are safe as are other antidepressants not in the list above. Antihistamines other that the last two in the above list are safe.  Neuroleptics such as olanzapine (Zyprexa), quetiapine (Seroquel) are safe as well. Stimulants such as amphetamine(Dexedrine, Adderall)  and methyphenidate(Ritalin, Concerta) are safe.  Questions regarding these drugs account for many phone calls.  I have at all times at least 20 patients on some combination of a stimulant and an MAOI without adverse effects.  This issue was studied by Fawcett et. al. and Feighner et. al.  Inquires sometimes focus on Fentanyl which has weak effect on serotonin through its action on the µ receptor  but can be used safely even though the FDA considers it to be contraindicated. Again, analgesics that lack serotonin reuptake properties are thus safe and include aspirin, acetaminophen, nonsteroidal anti-imflammatory drugs, codeine, oxycodone buprenorphine, morphine, and the aforementioned fentanyl.