(article originally published in the Naturopathic Doctor’s News and Review in April 2013)
Depression is defined, in Stedman’s Medical Dictionary 25th edition, as a reduction of the level of functioning. It is also defined as a sinking of spirits so as to constitute a clinically discernible condition. Endogenous depression is further defined as a descriptive syndrome for a cluster of symptoms and features occurring in the absence [or what seems to be] of precipitants. However one describes it depression will affect most everyone sometime in there lives. Stedman’s goes on to define reactive depression as a psychological state occasioned directly by an intensely sad [or challenging] external situation, relieved by the removal of the external situation. In the latter definition we might define depression not as a disease but more a great sense of unacceptable dis-ease.
It is obvious that depression can be defined as an abnormality of normal functioning of the body/mind/spirit and may be created by internal or external forces. Depression is a symptom, or set of symptoms, that allow the doctor to pinpoint a cause and treat the patient effectively. There are multiple possible causes of biochemical depression. Hypothyroidism, dehydration, inadequate protein intake, inadequate vitamin and mineral intake, cardiovascular disease, poor diet in general and inadequate digestion and absorption of food to name a few. Furthermore, drugs such as antidepressants may exacerbate depression. Environmental toxins such as mercury poisoning can cause depression. Life changes such as changes in jobs, loss of a love one, economic changes, or children leaving the home to go to school. The clinician bodes well to run standard labs such as a complete blood count, chemistry panel, hormone panels, and thyroid panels. A nutritional assessment is necessary. It is also well known that those that get regular exercise and drink at least 60 fluid ounces of water per day have fewer incidences of depression.
Why one is depressed is infinitely more important than whether they are depressed. Michael Davison, BSME, who has his own battle with depression, summarizes his journey, which I paraphrase, with these conclusions:
- Depression can be thought of as a friend…good friends don’t always say what we like.
- Good friends offer through mutual trust…understanding and insight.
- Depression is a consequence…an effect not a cause.
- One does not wipe out depression and live happily…one lives effectively and fulfillingly and depression rarely shows up. (1)
Dr. Viktor Frankl, the author of Man’s Search for Meaning and The Unheard Cry for Meaning, and others have probably done more to elucidate the most common cause of depression today. Dr. Bruce Levine, PhD, summarizes these thoughts:
- The rate of emotional difficulties and self destructive behaviors has increased since the advent of the Industrial Revolution.
- Our Genes have not changed…Society has changed.
- It can be argued that what we call a mental illness is actually a rebellion…more often passive than active…against an increasingly dehumanizing society in which consumption, production, and technology are worshipped at the expense of life.
- Society, as well as mental health treatment, has become radically industrialized and commercialized, resulting in a loss of historical antidotes to emotional malaise such as autonomy, meaning, and community.(2)
The standard medical model will always define depression as a disease. It will matter little why one is depressed… the solution will always be drugs. The Naturopath will ask the patient the obvious question…Why do you think you are depressed? And if the doctor will listen to the patient we will be able to communicate with the patient the most likely path of treatment. Most patients know exactly why they are depressed. And most standard medicine doctors don’t have the time to listen. In fact, only about 15% of the patients we see will have what is called endogenous depression, or the kind of depression that may have a genetic determinant. Even then many of these cases are treatable. One might not be able to change the gene…but we can give the gene a nutritional environment with which to optimize the gene’s ability to produce the neurotransmitters. Yet there are those that are severely mentally ill. One will find in there clinical practice that there will be some 5% that we don’t have an answer or solution in these cases.
A strong indicator of genetics playing a role in depression is the patients answer to why they might be depressed. The answer might come in this form: I don’t know doc seems like I have been depressed my whole life. Very few patients will say this. In my clinical experience these will be less than 15% of the cases you treat. Most people know exactly why they are depressed. This is born out by the recent research done on the efficacy of antidepressants. And since antidepressants remain the most used therapy in treating depression we must understand the truth about these drugs. In an analysis of six large studies done by JAMA researchers it was found that antidepressants only worked on the most severe cases of depression—13% of the people with depression. (3)
Using multiple meta-analyses, David Healy, M.D., reports that the studies show that 4 out of 5 patients treated with antidepressants would have improved on the placebo alone. Dr. Healy goes on to state,” One reason that antidepressants have been so commercially successful is that their lack of generalizable efficacy and their hazards are not apparent in journal articles.” (4) Furthermore, one of the tricks of the trade is to do a placebo washout. That is start both study groups on the placebo and eliminate those that improve on the placebo alone before starting the drug/placebo study. (5)
There are approximately 400 mental health diagnoses listed in the Diagnostic and Statistical Manual (DSM IV) of which we have no known biochemical/neurochemical etiology. And to treat these “disease states” we have numerous drugs that are utilized and none of these drugs have a clear mechanism of action in human beings. Antidepressants generally don’t work, yet they do bring in billions of dollars to those that make them. If antidepressants do work they can only use what you can produce—they in themselves do not increase the production of neurotransmitters. They do desensitize and down regulate the neurotransmitter receptors. They eventually cause down regulation of production of the very neurotransmitters they are supposed to support. So most commonly, even if the antidepressants seem to work in the beginning, they often fail over the long term requiring increases in dosing or the movement to other drugs of their class. Also, recently there have been some suggestions that anti-depressants can cause dependency. What is called “antidepressant discontinuation syndrome” when people try to quit them. In our clinical experience it is easier to detox patients from alcohol and street drugs than it is to detox them from Paxil, or other drugs of its class. It is far cheaper, in the long term, to medicate patients then it is to supply good quality counseling, nutritional guidance, or good quality health care. Several facts and truths about psychotropics are never told to the patient. This information is readily available to the doctor. First, we have no clear understanding how these drugs actually work in the brain. As one example, if we review the drug Prozac in the Physicians Desk Reference (PDR) we’ll see under the listing—mechanism of action— “UNKNOWN…but is thought to be…” This is true for over 90% of all psychotropic’s used today including the anti-anxiety meds. Secondly, research on these medications, for approval from the FDA, rarely have study groups larger than 400-600 patients and rarely exceed 4 months in length. In fact, if one looks at the PDR, the manufacturer of these drugs rarely approves their use beyond 4-6 months. Yet when the patient goes to the doctor they are commonly told that they may have to be on these medications the rest of their lives. Thirdly, medical professionals have absolutely no idea of the long term affects of these medications…and it is interesting that there is some research that indicates that the suicide rate in the US has risen consistently since the advent of Prozac in the early 1990’s. In fact, the research shows thatthe use of SSRIs will damage dopamine neurons over time (6).
Dr. Peter Breggin, M.D., psychiatrist, in his book, Brain Disabling Treatment in Psychiatry, 1997, clearly laid out the key principles involving psychotropic treatment. Treatments such as drugs, electro convulsant, and lobotomies are physical and they act to fundamentally change the normal brain and how it functions. These types of treatments always cause impairment in normal brain functioning sometimes permanently. Therapeutic results are ambiguous at best and often result in more impairment. Furthermore, these treatments cause impairment of normal brain functions in all patients that are exposed to them whether healthy volunteers or the mentally impaired. And since people are different genetically there are extreme variations on how people respond to these treatments. Dr. Breggin also points out that we have no known biological cause to most of these psychological ailments and furthermore, drugs are not specific for any disorder. These treatments more than often cause increased psychological and physical problems. In addition, the brain often tries to compensate for the chemical changes causing adaptations which cause the adverse reactions. When people withdraw from these drugs most will have withdrawal syndromes—euphemistically coined “discontinuation syndrome”. Patients with impaired brain function due to these treatments often display abnormal thinking. And the doctors who prescribe these medications either have unrealistic expectations or fail to inform the patients and then inherent dangers of using them (7). The take home message here is—we have numerous mental disorders listed and we don’t have a known biochemical etiology for any one of them…furthermore, we have numerous drugs to treat these disorders and we don’t exactly how they work or how they will work on any one person.
So the next real question. If I in fact want to treat brain neurochemistry with drugs are these drugs selective and only working in the brain? No, is the answer. Neurotransmission is global and systemic. Changing neurochemistry in the brain changes biochemistry and neurochemistry of every major organ system. Gut function changes. Production of melatonin and sex hormones are effected. Blood circulation and the ability to react to stressful events change. It is clear that psychotropic drugs affect the production, release, reuptake and utilization of systemic neurotransmitters. Although the mechanism of action of these medications is commonly different than that of street drugs and alcohol, they still affect the same neurotransmitters leading to prolong dysfunction of brain/body neurochemistry. A mind out of biochemical focus cannot find resolution for the patient’s individual issues. As long ago as 1969, terms were being used about a protracted withdrawal syndrome. Today, this is known as post acute withdrawal syndrome (PAWS). The idea behind PAWS is that the average patient continues to have underlying symptoms of withdrawal long after the original drug or alcohol has been metabolized out of the system. These symptoms can include depression, lack of concentration, mental fogginess, anxiety, sleep issues, fatigue and immune system dysfunction. It is also noted in the literature that these symptoms can last from six months to two years in the average patient if they do nothing more than just quit the drug or alcohol. While PAWS has been noted in the literature for street drugs and alcohol, it is also true for psychotropic medications for which it is called a ‘discontinuation syndrome’ (8).
The fact that nutrition has been often overlooked in the past in the areas of pharmacology, standard medical practices, and the treatment of mental health issues is not surprising. More than two-thirds of the medical schools in the United States still do not have a specific nutrition course in their curriculum (9). This ongoing failure to teach nutrition and practice nutritional medicine is embedded in the idea that we get our recommended daily allowance (RDA) of nutrients if we eat within certain defined parameters. There is a clear understanding now that even RDA’s of these nutrients, established by the Food and Nutrition Board of the National Academy of Sciences (NAS) in 1941, may keep subclinical disease states subclinical. Because the RDA’s for vitamins are minimum amounts that will only prevent the signs and symptoms of deficiency diseases, the daily intake should often be higher than recommended. This is especially true for treatment of depression. Furthermore, however well RDA’s work as a guideline, for any given person, they may be an underestimate or overestimate of the amounts actually needed for any specific health problem.
Dr. Marty Hinz, M.D., recognizes that there are two possible categories of nutritional deficiencies: Absolute nutritional deficiency and relative nutritional deficiency(10). An absolute nutritional deficiency occurs because dietary needs are not met. Relative nutritional deficiencies exist when dietary intake is sufficient but the needs of the system require more. Dr. Hinz concludes that most patients suffering from neurotransmitter problems have a “relative nutritional deficiency involving serotonin and dopamine amino acid precursors”. So it is logical, that in order to supplies the substrates to balance the monoamine neurotransmitters one has to increase the necessary amino acids that produce these molecules. However, treating with just one amino acid precursor is not much better than treating with Prozac. You cannot treat a relative nutritional deficiency with one nutrient. In fact, 5-HTP done as a stand-alone will deplete dopamine by inhibiting tyrosine Hydroxylase (11).) If one chooses to use amino acids to treat depression than both the serotonin side and the dopamine sides must be treated at the same time. These two sides keep each other in check and balanced. Treat one sided and we will see more failures than successes. Less than 10-15 % of your patients will ever respond fully to singular nutrient treatment. Some physicians will overwhelm their patients with multiple regimes and nutrients. One must keep this simple and work their way into the level of complexity each individual patient needs for their case.
We have standardized our beginning protocols and find that 80-85% of the patients we put them on respond favorably.
These protocols are based on one fact. The primary neurotransmitters—master neurotransmitters—are serotonin, dopamine, nor-epinephrine, and epinephrine. GABA can also be considered in this process. Every biochemical process in the human body depends on the proper levels of these neurotransmitters. When we bring these back into balance most other biochemical and neurochemical processes come back into balance. These neurotransmitters do not exist only in the brain—in fact only 5% of the serotonin is found in the mind. Serotonin is the primary gut neurotransmitter and also regulates clotting function and has a role in cardiovascular health. Nor-epinephrine and epinephrine also are produced in the adrenal glands to help us deal with stress. Nor-epinephrine is also critical in the production of the sleep hormone melatonin and the production of sex hormones. These are ‘Global” neurotransmitters involved in every major function of the biochemical reactions in the human body/mind. It is rare that we can treat just one of these neurotransmitters and expect everything to work normally—nothing works in a vacuum—and every biochemical process is intrinsically tied to every other process. Get the master neurotransmitters balanced, and in tune with the others, and all other processes move toward balance. In the past we used multiple formulas for multiple issues. The more that I reviewed this process over the last 10 years the more I thought how simple this could really be. The type of drug was not the major issue—bringing back the balance in these neurotransmitters was the issue.
Our standard starting amino acid protocols are as follows:
1) A good one a day multivitamin with a decent Vitamin B complex
2) A good mineral complex
3) At least 1000 mg of fish oil twice per day
4) 120 mg of 5-HTP twice per day
5) 1200 mg of Tyrosine twice per day
6) Depending on the patient response to the above we may add 300 mg of Mucuna pruiens twice per day, a source of
natural L-dopa which by-passes the rate limited step of tyrosine to l-dopa
7) 800 mg of methionine twice per day to produce SAM-e
8) Occasionally we might add 1000 mg twice a day of Glutamine to this formula.
9) 1000 mg of Vitamin C twice per day
As a note, we make this up as a morning/evening dose kit for patients so that the dosing can be done twice per day as a 1 month supply. This increased compliance and improved treatment results dramatically.
The power and legacy of naturopathic medicine is not just in the modalities we utilize to help the individual patient. The power and legacy of naturopathic medicine has always been to treat the whole person…Body/Mind/Spirit. And the spiritual is commonly overlooked in the initial phases of treatment. This is common because as we work with patients with multiple issues the conversations with the patient hardly ever lead to discussions of their spiritual beliefs. It is important to understand that the word spirit comes from the Latin word spiritus, which means a breathing, a life soul. Or, literately…to breathe. In Dr. Frankl’s many books he often talks about “the great sense of emptiness” that seems to plague the current human population. In fact, in most of the cases it is this great sense of emptiness…this lack of purpose and meaning that drives alcoholism, drug addiction, depression and anxiety in the majority of these cases. The spiritual issues must be broached with the patient in order for us to ascertain exactly the cause of the depression. The great sense of emptiness is more about the lack of purpose and meaning in the patient’s life.
Finally, the physician must be capable of counseling the patient. There are times when it is appropriate to send the patient to a psychologist for extensive counseling, especially for those cases that involve stark emotional and sexual trauma. Yet, the best way to think of counseling comes in the following statement, “The best counselors are those who know what you are going though, not those that have all of the answers. You don’t have to be an expert to help someone else. You just have to be real”(12).. The patient often needs a forum to express their fears and feelings. This commonly is not available to them in their homes or work places. Many just stuff their emotional issues and thereby make the depression or anxiety worse. The ability of the physician to listen without judgment, with compassion, and to be sensitive to the needs of the patient is often all it takes to help break the chains of depression.
Naturopaths have multiple tools at their disposal to treat depression: Acupuncture, homeopathy, physical medicine, herbal medicine, and nutritional medicine. In my practice we have utilized them all. But the mainstay of our focus on treatment has always been nutritional medicine. Without bringing biochemistry and neurochemistry back into proper balance then little is accomplished. A patient with a good solid bio/neurochemical foundation will often find the inner strength to find resolution for their mental and spiritual challenges. Nutrition is the foundation of all body biochemistry, including that of neurochemistry. Nutrition supplies us with the basic repair supplies which include proteins (amino acids from proteins are the building materials for neurotransmitters), carbohydrates and fats. Also essential are the vitamins and minerals which act as the essential co-enzymes and co-factors which facilitate the movement of the human biological system back to normal function. In fact, many vitamins and minerals serve as co-factors and co-enzymes for the production of neurotransmitters from amino acids. Our mainstay for treating depression and other mental health issues has always been IV nutrition and focused amino acid therapy. The IV’s are almost always standard nutritional IV’s.
A.M. is a 57 year old female patient that first came to see us in January, 2008. Her major complaints at that time were menopausal symptoms, extreme fatigue, mental fogginess, episodic mental confusion, past history of Graves’s disease, and episodic depression. She had been put on several antidepressants over the years and didn’t like them because they flatten her emotionally and decreased her sexual libido “to nothing”. She had self medicated for years with 4-6 alcoholic drinks daily and occasionally smoking marijuana. She quit alcohol and marijuana in January 2007 has been in recovery since then. She works a strong personal spiritual program and attends 12-step meetings. For 18 years, prior from moving from Florida to Arizona, she was a first and second grade teacher teaching English as a second language. She found the work rewarding but was often overwhelmed with the paper work and extra work required to successively complete her mission. After relocating to Arizona in 2007 she went back to school and is now a licensed massage therapist and loves her new beginning. Her initial labs revealed hypothyroidism (TSH 6.81) and high cholesterol (281). Her thyroid issues were successfully treated with natural thyroid hormone. Her cholesterol tends to be erratic but controllable with a strict diet and red rice yeast. Her menopausal symptoms were controlled with bio-identical hormones although at this date she no longer needs them. Over the next 2 years she did well physically with more energy and had received acupuncture and homeopathic treatments. Yet, she still had episodic episodes of depression and mental confusion. In January, 2010, we started her on a nutritional protocol that included IV therapy (standard nutritional) and focused amino acid therapy. Three days later she stated, “I can’t believe how much better I feel.” She has continued to do the amino acid protocols to this date although now she is half dosing the amino acids and continues to do well. The few times she has discontinued them the prior symptoms reappeared. To some degree this case represents what we might conclude as having a relative nutritional deficiency. Less than 5% of our patients have to continue the protocols although some will do them for several months before discontinuing the treatment.
E.W. is a 52 year old Native American male that first came to see us in March, 2004. At that time he was in recovery from alcoholism times 17 years. The year before, he suffered the loss of his Grandmother (his spiritual teacher), two of his favorite aunts, and his Father. His personal relationship with his girlfriend had also ended. His depression was “off the charts” and the staff at the local college where he teaches urged him to seek help. E.W. not only practiced his Native ceremonies but also attended church regularly and considered himself to be a strong Christian. “I’ve tried counseling but nothing seems to work”. At the time of the interview I asked EW if he had taken time to grieve his losses. He responded by saying, “no, I have to be strong for my family”. We talked extensively on the need to grieve. Those who stuff their grief will always be depressed. As a physician I have this talk with many patients. To grieve is not an abnormal human experience. It is a necessary human experience. To grieve is to heal. His labs were all in the normal range. We started him on basic IV nutritional therapy and the amino acid protocol with instructions to find his “sacred space” and allow himself to feel his losses. We revisited two weeks later and his comments at the time were, “feel wonderful” and “feel like I am back into life: We continued seeing him weekly to biweekly for the next few months. It took him about 4 months to finally come to peace with the loss of his relationship and we continued to treat him over that time. He continues to be a patient for general health issues. It is not uncommon for us to meet and just talk about “life”. He continues to do well. This is a common case of perceptual/situational depression.
LL is a 47 year old female that first came to see me September, 2012, with a diagnosis of fatigue, fibromyalgia, brain fog, insomnia and depression. She experienced depression over her lifetime due to growing up with her “angry and bitter grandmother”. She still had a deep seated anger at her grandmother who had passed away years ago. Patient grew up poor in rural Mexico. Patient is married and has a “wonderful relationship” with a caring and loving husband. I had a long discussion with her and her husband about nutritional treatment and also about the need to resolve her anger. Vitals were in the normal ranges and chemistry panel and complete blood count were normal. Patient was currently on Cymbalta 40 mg per day (a serotonin/norepinephrine reuptake inhibitor), Lyrica 100mg a day, and Ambien 10 mg for sleep. The patient and her husband were going on vacation and would be gone about 2-3 weeks. She wished to get off all drugs. When we see drug regimes such as these we do one drug at a time. Antidepressants are always a step down over time. We started the patient on the amino acid protocol with the Mucuna (because Cymbalta and drugs in its class have strong actions on norepinephrine) with instruction to reduce her Cymbalta by ¼ dosing every 10 days. We revisited one month later after the family got back from vacation. We started her on weekly nutritional IV’s and continued the amino acid treatments. One week after starting more focused treatment she reported a “huge increase” in energy and actually played soccer with her children. At this point she was doing 5 mg of Cymbalta per day. She started doing 5 mg of Cymbalta every other day and one week later suspended dosing the drug. Over the holidays had some depression “creep” in due to memories of more difficult times yet continued therapy and has rebounded. Overall fibromyalgia pain has reduced by 90% and patient feels more grounded emotionally. She continues treatment on a biweekly basis and has made contact with counselors who are helping her work through her anger issues.
One of the first questions usually asked by physicians wanting to use amino acids protocols in treating depressed patients is—What about serotonin syndrome? Serotonin syndrome is caused by an overabundance of serotonin in the central and peripheral nervous systems and has a constellation of symptoms which may include:
- Cognitive effects: headache, agitation, hypomania, mental confusion, hallucinations, coma
- Autonomic effects: shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea.
- Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor.
There is no laboratory test for serotonin syndrome. Therefore diagnosis is by symptom observation and investigation of the patient’s history From Wikipedia, the free encyclopedia
Over the last 12 plus years we have treated many patients with the issues pointed out in these case studies including detoxing them from unnecessary antidepressants. The most common cause of serotonin syndrome is an intentional overdose of antidepressants (13). In using combination amino acids and treating both the serotonin/dopamine sides we have never seen serotonin syndrome. Our protocols mirror those of Dr. Marty Hinz, M.D. of Neuroresearch who undoubtedly one of the leading experts in the country on amino acid treatment. Serotonin syndrome is a possibility if one treats just the serotonin side…especially if the patient is on a selective serotonin reuptake inhibitor at the same time. We have never seen this using combination amino acid treatment. However, if you suspect serotonin syndrome in your patient have them seek immediate emergency treatment. Benzodiazepines and serotonin receptor blocking drugs are the common treatment.
In conclusion, nutritional therapy can be a complex issue. Using the “shotgun approach” is often worse than the singular nutrient approach. Clinician’s that wish to pursue this level of treatment for their patient must understand extensive information on metabolism and genetic function. Without understanding the intricacy of molecular functions, and how they are activated and manipulated through nutritional treatment, the clinician is more likely to create more harm than good. Even if harm is not caused to the client, treatment often fails to produce the desired result. Just taking one particular vitamin, or amino acid, to address mental health issues is much akin to supplying the client with just Prozac to “cure” their depression. Dr. Majid Ali M.D. says it best:
…No molecule exists in biology alone, functionally or structurally. This is self evident. And yet we physicians insist in diagnosing “a nutrient deficiency” to understand “a disease” which we can then treat with a “a nutrient therapy”…The central issue here is: Mono-nutrient therapy has no place in the clinical practice of molecular medicine. (14)
- Calling, Recalling, and Restoring the Signal Function of Emotions, in Ethical Human Psychology and Psychiatry, Vol 7 Number 3, Fall/Winter 2005, Page 225.
- Mental Illness or Rebellion? Ethical Human Psychology and Psychiatry, Vol 7, Number 2, Summer 2005, Pages 125-129)
- As reported by Sharon Begley, The Depressing News about Antidepressants, Newsweek, Feb 8, 2010.
- The New Anecdotes. Ethical Human Psychology and Psychiatry, Vol 9, Number 3, 2007, Pages 131-137.
- Timothy Scott, PhD. Tricks of the Trade. Ethical Human Psychology and Psychiatry, Vol 8, Number 2, Summer 2006, Pages 133-144.
- Prozac Backlash, Joseph Glenmullen, 2001, Pages 42-43.
- Brain Disabling Treatments in Psychiatry. Springer Publishing Company,. LLC.11 West 42nd Street, New York, NY, 10036. Pages 1-10.
- Tamam, Lut; Ozpoyraz, Nurgal. Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Review. Ethical Human Psychology and Psychiatry. . 19 (1): pages 17-26.
- C Lo: Integrating nutrition as a theme throughout the medical school curriculum. American Journal of Clinical Nutrition 2000, 72:882s-889s.
- Marty Hinz, et. al., Relative nutritional deficiencies associated with centrally acting monoamine. International Journal of General Medicine, April 10, 2012. (www.NeuroResearch.com)
- D.K. Zhelyaskov, et.al., Tryptophan Derivatives as Inhibitors of Tyrosine Hydroxylase in Vivo and in Vitro. Molecular Pharmacology, 4, 445-451, Feb 2, 1968.
- Todd Burpo. Heaven Changes Everything. Page 37.
- Mayo Clinic (Online). Mayo Clinic, Serotonin Syndrome.
- Majid Ali, M.D.: Intravenous Nutrient Protocols in Molecular Medicine. In: Nutritional Medicine: Principles and Practice (unpublished manuscript, 1994). Institute of Preventive Medicine. 95 East Main Street, Denville, New Jersey 07843. pp 6-7.