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Diane Bilodeau Ph.D., Project Manager, Scientific Affairs
Atrium Biotechnologies Inc.

Alain Thibodeau Ph.D., Director, Scientific Affairs
Atrium Biotechnologies Inc.

in collaboration with Dr. Alan Pressman, DC, DACBN, CCN
Grammercy Health Associates

Abstract

Anxiety is a common plague in our performing post-industrial society. Anxiety disorders have many faces but share similar disturbances in the brain network. Deregulated firing of neurons translates into psychological and physical stress that may seriously impair one’s life. Pharmacological therapy is available. Benzodiazepines, buspirone, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants are commonly used to treat these disorders. For those seeking more natural therapies, valerian, St-John’s wort and kava have, so far, represent alternatives. All these therapies have their drawbacks and have been associated with potential harmful side effects. Casein hydrolysate is a new natural alternative with proven in vitro and in vivo anxiolytic activity.

What is Anxiety?

Anxiety is defined as an uneasiness state of mind over an anticipated painful event not under the subject’s control. The psychological stress is often accompanied by unpleasant physical sensations. Anxiety is a normal adaptive response to a stressful situation. Any student would confirm that a certain level of stress helps performing at college exams. Such anxiety is event-related and resolves shortly after. Anxiety becomes a disorder when excessive in terms of intensity and duration or not linked to any objective threat.

Pathologic anxiety presents with various manifestations. In any case, the brain circuitry is affected in similar ways. Anxiety creates disturbances in the cerebral cortex, affecting connections between brain structures within the limbic system and other neural bodies. The neurotransmitters primarily associated with anxiety in these regions are serotonin gamma-aminobutyric acid (GABA), and norepinephrine. Conventional pharmacological as well as alternative therapies, by modulating neurotransmission, may help normalize brain activity.

The Many Faces of Anxiety

Generalized Anxiety Disorder

Generalized anxiety disorder is a problem shared by up to 4% of the population. It manifests as a diffuse sense of worries spreading wastefully over all aspects of one’s life. It seems like sufferers cannot ever stop their mind from thinking “what if”. Any minor life stress or frustration and, even eventually a lack of any, will feed such restless minds. This overwhelming brain activity comes with a price. Sleeping problems, difficulties to concentrate, headaches and irritability are common traits. It also puts a lot of pressure on loved ones, who are kept constantly tagged in the fear of a deadly event.

Panic Disorder

Panic disorder (PD) affects about 5% of the population usually starting in late adolescence or early adulthood with predominance among women. People with PD experience episodes of acute terror coming out of the blue. Common symptoms include chest pain, shortness of breath, increased heart rate, cold sweat, dizziness, and shaking. Most sufferers on their first episode genuinely believe they are having a heart attack for which they are most likely to rush to the closest hospital emergency room. Eventually learning that there is nothing wrong with their heart is usually confusing and tells a person not trust her/his own mind and body to correctly monitor reality.

Agoraphobia

About one-third of people with PD will develop a condition called agoraphobia. The term is misleading though. Agoraphobia may include, but is not restricted to, a fear of open spaces. Agoraphobia is best described as the fear of fear and arises from avoidance of places or situations where panic attacks have occurred before. Unfortunately, avoidance behavior raises a feedback loop leading to more panic attacks. As the pattern of attacks extend the “safe zones” where an agoraphobic is panic-free tend to shrink. In extreme cases, some people will end housebound, unable to face their fear of the outside world.

Social Phobia

Social phobia is the most common anxiety problem. It rises from the unjustified fear of being watched and judged in social or performance situations. Blushing, sweating, and freezing in social situations are common symptoms of the disorder. Social phobic may avoid talking, writing, eating or drinking in public. They develop a sense of being unfit and tend to avoid all contact with others whenever possible.

Specific Phobias

It is estimated that 12% of the population will experience a phobia at some point in their lives. Phobias are irrational fear that can rise against almost any specific object or situation (e.g., flying, heights, animals, injection, blood). Contact with it can evoke panic with symptoms as shortness of breath, flushes, heart palpitations, sweating, dizziness, nausea and confusion.

Obsessive Compulsive Disorder

Obsessive-compulsive disorder (OCD) affects a little more than 2% of the population. The symptoms typically begin during the teenage years or early adulthood and consist of unwanted persistent thoughts (obsessions) leading to senseless repetitive behaviors (compulsions). The compulsion is aimed at relieving the discomfort caused by the obsessions. In severe cases, a time-consuming ritual may hamper normal living.

Post-Traumatic Stress Syndrome

Approximately 25% to 30% of individuals who suffer or witness a traumatic event (such as rape, war, natural disasters, severe accidents, terrorist attacks) will develop chronic posttraumatic stress disorder (PTSD). Symptoms may include flashbacks of the trauma, nightmares, insomnia, depression, emotional numbness, irritability and survivor guilt. PTSD sometimes develops months after the event that triggered it. Recovery typically takes time.

Treatments

A) Pharmacotherapies

Benzodiazepines:

Benzodiazepines (alprazolam, lorazepam, diazepam) are the most commonly used drugs for treating most anxiety disorders. Benzodiazepines bind GABA receptors at a site different than GABA itself. Allosteric binding of these agents potentiates GABA inhibitory neurotransmission and thus relieves anxiety symptoms. Benzodiazepines have short-half life and high therapeutic index. In addition to their anxiolytic effect, some benzodiazepines exhibit anticonvulsant and muscle-relaxant properties. Nevertheless, benzodiazepines present a high risk of physical dependence and since they are metabolized through the hepatic microsomal system, they may interfere with other drugs. Adverse effects are depressed CNS, delayed reaction time, and forgetfulness.

Buspirone

Buspirone precise mechanism of action is not well characterized. It binds a specific subset of serotonin receptors but is suspected to act on the dopaminergic system as well. Buspirone is as efficient as benzodiazepines in reducing anxiety symptoms, has the advantage over them not to produce withdrawal symptoms, but lack their muscle-relaxant properties. Buspirone is not sedative and has only minor cognitive and psychomotor adverse effects. Side effects are few and may include nausea, headache, dizziness, nervousness, lightheadness, and excitement. Due to a delayed onset of action, buspirone is of little use in panic disorders. Its activity is also limited in patients recently withdrawn from benzodiazepines. Buspirone should not be used concurrently with MAOIs as it raises a risk for increase blood pressure.

Selective Serotonin Reuptake inhibitors (SSRIs)

SSRIs (fluoxetine, fluvoxamine, paroxetine and sertraline) act by preventing the reabsorption of serotonin at the presynaptic neuronal membrane. As a consequence, the available supply of serotonin is increased in the brain, improving the serotonergic transmission. SSRIs have antidepressant and anxiolytic activities. Clinical indications included PD, agoraphobia, OCD, PTSD and social phobia. SSRIs usually have mild side effects. They may cause anorexia, nervousness, insomnia, diarrhea, nausea, dizziness, dry mouth, and a range of sexual dysfunctions. Combined use of SSRIs and MAOIs is contraindicated.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs (phenelzine, tranylcypromine, isocarboxazid) interfere with the breakdown of neurotransmitters within the synaptic cleft through inactivation of the monoamine oxidase enzyme. As a result, serotonin, dopamine and norepinephrine accumulate at this location. This causes activation of serotonin and norepinephrin receptors. MAOIs are helpful in reducing panic attacks, elevating depressed mood, and can also help with social phobias. Side effects include blurred vision, constipation, drowsiness, dry mouth, insomnia, hypotension and weight gain. MAOIs are non-addicting but have the potential for severe pathophysiology. Overdose causes catecholamine poisoning, resulting in hypertension, tachycardia, tremors, seizures, and hyperthermia. MAOIs also interact with other drugs and foods containing tyramine. The use of MAOIs tends to be abandoned to the profit of less toxic anxiolytics.

Tricyclic Antidepressants (TCAs)

TCAs (clomipramine, amoxapine, amitriptyline, maprotiline, desipramine,imipramil) block serotonin, dopamine and norepinephrine reuptake into the neuron, so that the monoamines remain active longer. TCAs may be useful in treating PD, agoraphobia, social phobia and PTSD. Common side-effects include weight gain, blurred vision, constipation, dizziness, drowsiness and dry mouth. Cardiovascular effects are also associated with these medications. TCAs are less well tolerated than SSRIs and may cause withdrawal side-effects. Tricyclics are highly dangerous in overdose and should no be used concurrently with MAOIs.

B) Alternative therapies

Valerian

Valerian (Valeriana officinalis) extracts have sedative and anxiolytic properties. Clinical trials support its effectiveness in treating a wide range of stress conditions. Valerian’s mode of action is similar to that of the benzodiazepines and results from weak binding to GABA receptors. Chronic use of high doses can lead to withdrawal symptoms. The FDA recognizes Valerian as safe. Nevertheless, drivers and operators of heavy machinery should use Valerian with caution due to its vigilance-decreasing effects. Long-term use may be associated with headaches, restless states, sleeplessness and cardiac disturbance. Valerian can inhibit the cytochrome P450 and thus is susceptible of interfering with the metabolism of some drugs.

St-John’s Wort

St-John’s Wort (Hypericum perforatum) medical history goes back to ancient Greece. The herb has pleiotrophic effects but is most famous for its anxiolytic and antidepressant properties. This is supported by a cohort of clinical studies although some recent study has seriously raised doubts about the herb efficacy. Current research suggest that St. John’s Wort extracts may act by impairing the reuptake of the neurotransmitters serotonin, norepinephrine, and dopamine all together. The hyperforin constituent of St John’s Wort is suspected to be mainly responsible for this inhibition. St-John’s Wort is usually well tolerated but unfortunately due to a strong inhibition of the cytochrome P450 the herb has a high profile of potential interactions with drugs. The FDA has emitted a warning at this effect.

Kava

Kava (Piper methysticum) is native to the south Pacific where it was traditionally consumed as a drink, as part of some rituals, for years before the first European explorers discovered it. Kava is anxiolytic and sedative but without inducing apathy. It also is an excellent muscle relaxant. Several clinical studies have provided evidence of kava effectiveness for these applications. The kavalactones components of kava are believed to be responsible for the psychoactive activity of the extract. It is postulated that kavalactones work through potentiation of GABA transmission and inhibition of noradrenaline uptake. Kava has received a lot of attention worldwide recently when some deaths, due to liver failure, were reportedly associated with the use of kava. As a consequence, kava was banned in several countries, while others (including USA) simply warned the population against the potential risk of severe liver injury associated with the use of kava.

Casein Hydrolysate

Milk has always been a little more than food to humans. Maybe as a reminiscence of our early childhood, drinking warm milk is believed to provide a calming effect. Recent research studies have provided a scientific ground on which to raise that belief to the rank of fact. This all started when casein, the major milk protein, was hydrolysed, in a controlled manner, into small peptides. When screened for anxiolytic activity, one of the peptides strongly lit up the assay. The active decapeptide was isolated and its spatial structure, as determined through NMR spectroscopy and molecular dynamic simulation, revealed an amazing similitude to that of benzodiazepines. Indeed the peptide was shown to bind GABA receptors in test tube assays.

Figure 1

Animal studies confirmed that the decapeptidealso had in vivo anxiolytic properties. In the “conditioned defensive burying test” for anxiety, animals treated with the peptide had significantly decreased anxiety score when compared to those who received either Saint John’s Wort or Kava. The peptide-treated animals had in fact similar scores as those obtained by diazepam-treated animals.

Figure 2

The second trial was aimed at evaluating the effect of the peptide on some physiological responses to stress in healthy volunteers. In one test, subjects were asked to complete a color test performance (Stroop test) after taking the peptide. Their plasma level of cortisol (ACTH) was evaluated throughout the test, as a measure of stress. Under the conditions of the tests, ACTH levels of control subjects tended to increase, while no raise in the ACTH level was observed in the group who received the peptide (Figure 3). Peptide treatment had no effect on the subject’s performance per se.

Figure 3

Conclusion

There is hope for people afflicted with one of the many forms of anxiety disorders. Besides psychotherapeutic treatments, which were not the focus of this article, pharmacological and alternative therapies may offer some relief.

Anxiolytic pharmacologic drugs are very powerful. Unfortunately their use is associated with several undesirable and potentially threatening side effects. For those who prefer a more natural approach to treatment, herb extracts have traditionally been the only alternative. The problem with extracts is that, either they work too well, as kava, and are potentially dangerous, or they are not potent enough and work at best as a placebo.

Casein hydrolysate offers a new natural alternative. It has clinically proven anxiolytic activity without side effects. It is readily absorbed. The anxiolytic effect is immediate and may last up to 6 hours. The product also has very low allergenicity since the protein is hydrolysed. It does not cause addiction or withdrawal symptoms and does not interfere with medication. Casein hydrolysate is commercially available as a dietary supplement under the name Procalm^TM.

References

Lecouvey M, Frochot C, Miclo L, Orlewski P, Marraud M, Gaillard J-L, Thon Cung M, Vanderesse R. Conformational studies of a benzodiazepine-like peptide in SDS micelles by circular dichroism, H NMR and molecular dynamics simulation. Letters in science, 4 (1997) 359-364.Lecouvey M, Frochot C, Miclo L, Orlewski P, Driou A, Linden G, Gaillard J-L, Marraud M, , Thon Cung M, Vanderesse R. Two-dimensional H-NMR and CD structural analysis in a micellar medium of a bovine αsi-casein fragment having benzodiazepine-like properties. Eur. J. Biochem. 248 (1997) 872-878.Miclo L, Perrin E, Driou A , Papadopoulos V, Boujrad N, Vanderesse R, boudier JF, Desor D, Linden G, Gaillard J-L. Characterization of alpha-casozepine, a trypic peptide from bovine alpha (s1)-casein with benzodiazepine-like activity. Laboratoire des Biosciences de l’Aliment UA 885 INRA, Faculté des Sciences, Université Henri Poincare-Nancy 1, Vandoeuvre-les-Nancy, France. FASEB J 2001 Aug ;15 (10) : 1780-2.