Agoraphobia is often associated with panic disorder and represents one of six major anxiety disorders described in DSM-IV (the Diagnostic and Statistical Manual of the American Psychiatric Association – arguably the most commonly used classification system in contemporary psychiatry). The other major anxiety disorders include Generalized Anxiety Disorder, Obsessive-Compulsive Disorder (described in the Winter 2003 Islamica edition), Social Phobia, Specific Phobias, and Post-Traumatic Stress Disorder.

DSM-IV defines Agoraphobia as: “Anxiety about being in places or situations from which escape might be difficult or in which help may not be available in the event of having a panic attack or panic-like symptoms. Agoraphobic fears typically involve situations that include being outside the home alone (as in José’s case), being in a crowd, standing in a line, being on a bridge, or traveling in a bus, train or automobile.” Crowded shopping centers, sports stadiums and underground subway cars are particularly difficult for people with agoraphobia.

When found in one of these situations, the agoraphobic fears that he may develop a panic attack. A panic attack is “a discreet period of intense fear or discomfort in which four or more of the following symptoms develop abruptly and reach a peak within 10 minutes.”

1. Palpitations or accelerated heart rate

2. Sweating

3. Trembling or shaking

4. Shortness of breath

5. Feeling of choking

6. Chest pain or discomfort

7. Nausea or abdominal distress

8. Feeling dizzy, lightheaded or faint

9. Derealization (feelings of unreality) or Depersonalization (being detached from oneself)

10. Fear of losing control or going crazy

11. Fear of dying

12. Paresthesias (numbness and tingling)

13. Chills or hot flashes

José was in full panic mode when he arrived at my office. As is usually the case with these events, the anxiety slowly diminished over time and within a few minutes he was able to engage in therapy.

All of this occurred early in my psychiatric career while I was still under the influence of two powerful schools of thought – the Psychoanalytic school that firmly believed that these anxieties were determined by childhood experience and internal psychic conflict; and the Anti-psychiatry school of Laing and Cooper that disliked traditional psychiatric treatments, especially medication, and tended to see all psychiatric problems as primarily of social and familial origin.
Psychiatry has evolved considerably from those days in the early 1970s. For example, in the 8th edition of Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, the “bible” of the psychiatric resident and medical student, the section on the psychodynamic view of anxiety is one of the shortest and contains almost no analytic theory. This is a sign of the times, as psychoanalysis is being marginalized in favor of biological psychiatry and cognitive-behavioral therapy, which has taken over as the most “evidence-based” form of non-medication therapy.

In the case of José, these changes would have important practical implications for treatment. Nowadays, in all likelihood, he would be treated with some combination of medication (probably one of the serotonergic agents in the Prozac family or possibly a benzodiazepine like Clonazepam) and a program of graded exposure to the feared situations known as Cognitive Behavioral Therapy. Ironically, this is what he ended up receiving anyway but the theoretical basis and the evidence for this approach were not as clear at the time.

Agoraphobia, especially in its form with panic attacks, elicits an extreme form of anxiety, which you can notice by looking at the symptoms. The overall prevalence rates of Panic Disorder in various studies range from 0.4 percent to 3 percent with a median value of 2.1 percent. Women outnumber men by at least 2 to 1. This is a considerable frequency given that Schizophrenia, for example, affects only 1 percent of the population. One should not minimize the suffering induced by this disorder even if the people affected remain relatively sane.

What is anxiety in reality? The Webster’s Dictionary defines it as “a state of being uneasy, apprehensive, worried about what may happen.” In modern times, our lives are bathed in anxiety. We can see it on the faces of people on the morning subway. We can see it on the faces of journalists in dangerous places such as Iraq and Afghanistan. And we can even see it on the faces of children insecurely attached to their parents because of parental preoccupations and excessive daycare hours – the neglected children of the two-careered parents.

So how do we distinguish Anxiety Disorders from “normal anxiety”? DSM-IV speaks of Generalized Anxiety Disorder, which is characterized by:

a) Excessive anxiety and worry occurring for at least six months about a number of activities such as work or school performance.

b) The person finds it difficult to control the worry.

c) The anxiety and worry are associated with three or more of the following:

1. Restlessness or feeling keyed up or on edge

2. Being easily fatigued

3. Difficulty concentrating or mind going blank

4. Irritability

5. Muscle Tension

6. Sleep disturbance

Generalized Anxiety Disorder corresponds somewhat to the old psychoanalytic concept of anxiety neurosis. Contemporary psychiatry has however made considerable effort to render its practice more reliable and more scientific. Thus it has operationalized the diagnosis with reproducible criteria. In this way, it is more feasible to do research on these entities and have some agreement as to the terms we are using. Despite some debate about the validity of Generalized Anxiety Disorder, it does seem to have held up to scrutiny as a robust and meaningful category.

When we look at the criteria of this disorder, however, most “normal” people can identify with the description, especially during stressful periods of their lives. It does appear to most observers of modern economies that our society consistently and repetitively generates stress. This subject will be pursued further in the section on social factors.


Jean was a patient of mine in his mid-40s – successful, intelligent, and socially conscious. Like many of his left-wing cohorts in the political activist groups of the iqjos and 80s, he had made his way into a middle-management civil service position that allowed him both a decent revenue and not to be too seriously in contradiction with his social values.

We had been through a lot together over the years – his wife’s battle with breast cancer, retinal detachment in one eye that the surgeons were unable to correct, anda rebellious, drug-dealing son who preferred hip-hop to Bob Dylan.

Through all these difficulties, Jean was able to manage his anxiety and rarely lost a day of work. But this time it was too much.

“I can’t take it anymore,” he stated matter-of-factly. “My anxiety is sky-high, I can’t even think straight.”

“What’s the problem?” I queried. “Is your son acting up again?”

“No, everything’s under control at home and the family harmony has never been better.”

“So, what’s up?”

“It’s work. The federal government has cut transfers to the province once again and we’re in severe cost-cutting mode.”

“Are you at risk of losing your job?” I asked.

“No, that’s not it,” he answered, patiently enduring my premature questions. “They’re merging services and my new boss is from another department. He’s trying to protect his own people and push our group out.”

“Can’t you do anything about it? Where’s the union?” I queried, trying to remain optimistic.

“The union has become really passive. They’re all afraid of losing their own jobs. They don’t seem to be willing to do anything to defend us any longer.”

“What are you going to do?” I asked, hoping he would have the answers that I didn’t.

“I really don’t know. You know how important my work is to me. But I can’t continue this way.”

In fact, his situation had become medicalized. Jean was now paralyzed with anxiety and we had little choice but to put him on medical leave. However, the situation left me with a large question mark in my mind. “Where is the problem individual and where is it really social?” “How can we, as doctors, protect the individual from the toxic effects of social pathology – both physical and mental?” “What is our role as doctor or as human being for that matter?” Before addressing the question of the social origins of anxiety, let us return to our basic model, the bio-psycho-socio-spiritual model, in attempting to understand the etiology and potential treatments for anxiety.


Biological psychiatry has made enormous advances in the last few years, so much so that it would not be unfair to say it is the leading edge of the field. This has given psychiatry, as a discipline, considerably more credibility, especially in the world of science, than it had in previous epochs. The downside of scientific medicine, however, is that the desire to be objective, measurable, and verifiable has led to the loss of heart quality and humanity in medical practice.

One of the areas most affected by the evolution of science and technology has been genetics, which is at the core of biological psychiatry. Here again one confronts a certain conundrum. If human behavior is determined by our genes and chromosomes, where is the place of free will and choice in our lives? This debate, of course, is not limited to the field of psychiatry. Philosophers and theologians have argued this issue for centuries – free will versus determinism. Genetic studies in psychiatry may have an important contribution to make to this debate.

Let us look more closely at the various forms of genetic investigation, of which there are seven types:

1) Family Studies: These look at the familial nature of dis-ease. ivlost often this involves finding a “proband” (carrier of the disease or trait) and then looking for relatives (first-degree relatives and those more remote) and comparing the rate of disease among relatives against those in the general population.

For example, we find that the lifetime prevalence of Panic Disorder in the general population is 1 percent to 3 percent, but the rate among first-degree relatives is 7 percent to 20 percent – 2 to 4 times greater than in the general population.

In Generalized Anxiety Disorder, the prevalence rate in the general population is 3 percent to 5 percent. The risk to firstdegree relatives, however, is 6 times that of the general population. In Obsessive-Compulsive Disorder, the prevalence in the general population is 1 percent to 3 percent and among first-degree relatives, the rate is 3 to 5 times more.

We begin to see here that the familial tendency toward anxiety disorders is strong, although not as strong as that for Schizophrenia or Bipolar Disorder (formerly known as Manie-Depressive Disorder). This implies that it is often not appropriate to tell people to “cool down” or “chill out.” They may, in fact, not be able to do so as they are biologically programmed to overreact. It also implies a certain understanding and compassion for the different natures of people.

2) Twin Studies: These have given us considerable information on the genetic contribution to various psychiatric disorders. In these studies, we compare monozygotic twins (identical genetic makeup) to dizygotic twins (genetically just like ordinary brothers and sisters, i.e. 50 percent of genes in common). By comparing the two groups, we can arrive at an estimate of “heritability.” We can thus tease out the genetic contribution from the environmental one, which would be similar for both types of twins.

Results – the Virginia Twin Registry Studies found that monozygotic twins were concordant (both had the same anxiety diagnosis) in 24 percent of cases of Panic Disorder, versus only 1 1 percent for dizygotic twins. Combined with other studies, the overall results suggest that monozygotic twins are 2 to 3 times more likely to be concordant for this diagnosis than dizygotic twins. This was the only anxiety disorder for which the twin studies have been contributory. For other anxiety disorders, the twin studies have not given conclusive results.

3) Adoption Studies: In these studies, one compares the rates of disease in biological and adoptive parents of probands (those adoptees who manifest the disease). Although these studies have given interesting results in Schizophrenia, Bipolar Disorder, and Alcoholism, we still have little information about the anxiety disorders.

4) Cytogenetic Studies: These look for chromosomal abnormalities, but are not yet relevant for anxiety disorders.

The next three types of studies have emerged because of advances in science related to the Human Genome Project.

5) Genetic Linkage Studies: This kind of study looks for genes located near certain known markers on a given chromosome. The study identifies the general location of a gene rather than the gene itself.

6) Association Studies: These look for the co-occurrence of marker and disease in populations. These studies can narrow the focus of the location of genes as they extend for only a short distance on the chromosome. We are thus “zooming in” on the location without yet identifying the specific gene.

7) Gene Expression Studies: These studies are the definitive way to establish the role of a gene or set of genes in disease.

These genetic studies are still in the early stages of development. Possibly the most significant finding to date is the association of an anxiety trait (not a specific clinical disorder) and a chromosome region linked to the serotonin neurotransmitter system. The 5HT transporter protein that promotes serotonin re-uptake is encoded by a gene in the Q7 12 segment of chromosome 17.

We can begin to see here that despite all the “hype” about the Genome Project, it has not advanced us much in terms of understanding anxiety and has been even less useful clinically. Of course, there is the hope that one day this will all change. By this attitude medical science is often leading us down the proverbial garden path. It is as if the scientists are still promising us that one day we will have the answers for all major medical problems and human suffering will be obliterated. This flies in the face of the entire history of medicine, and of humankind for that matter. But “we are in a new era,” we are told, and everything is possible.

In fact, deeper observation and reference to holy texts from the beginning of time will instruct us otherwise. Illness and suffering are written into the hardware of life. Medical science may alter the details but the essential realities must remain as they were designed to be.


Another way of looking at the biological basis of anxiety is in terms of neuro-transmitter systems. From this model, we get the idea that many psychiatric problems are from a “chemical imbalance.” Although this concept is somewhat simplistic, it has a goodly amount of reality in it and it is one of the most useful models we have. There are two major implications of this model:

1) You don’t have to feel guilty for your symptoms as they are largely out of your control. I often like to compare major de-pressive or anxiety disorders to diabetes. In diabetes, you are lacking insulin. In depression and anxiety, you may be lacking serotonin or norepinephrine.

2) You may change your feeling state through medications, or chemical rebalancing, if you will. Nowadays, many people have objections to taking meds. “I don’t want to use chemicals,” they say, thus associating psychiatric meds with toxic chemicals like benzene or toluene or relating them to drugs of abuse like cocaine and crystal methedrine. Here again the diabetes model is useful and often enough the response to antianxiety meds may be almost as good as with insulin in diabetics. “If you were taking insulin for diabetes, would you consider yourself addicted?” I say to challenge their prejudices. When they respond in the negative, I continue “Then why would you feel addicted if you take Zoloft for anxiety?” Most people can get the point although we always have ideologues to contend with and then we are limited to psychotherapy, which may work only partially in many cases.
As in all instances of the scientific exploration of the human being, the picture gets increasingly complex the more it is studied. Whereas we originally believed that anxiety was mostly an issue of the noradrenergic system and the stress hormones, it has now extended to include the serotonergic system, neurosteroids, arginine vasopressin, neuropeptide- Y, galanin, and cholecystokinin, among others.

Since we will in no way be able to be comprehensive in this description, we will investigate only the four best known systems – the norepinephric, the hypothalamic- pituitary axis, the serotonergic system, and the GABA-benzodiazepine system. If you have difficulty following the chemical and anatomical descriptions that follow, do not get anxious. People trained in this area often get overwhelmed by the complexity and sophistication of the workings of the human organism. Such are the wonders of the creation and its magnificent Creator. Or is it just the random mutations of genes as our evolutionist scientists would have us believe?


This is the classical chemical stress response. Norepinephrine is responsible for increasing your heart rate and blood pressure when you sit in the dentist’s chair, fearful of the pain to come. The dentist then adds more noradrenaline to increase the effectiveness of local anesthesia. Some people may recognize the “rush” that occurs. Stress produces increases in norepinephrine turnover in the locus coeruleus, the limbic regions (hypothalamus, hippocampus, and amygdala) and the cerebral cortex. It is thought to be responsible for increased arousal as well as panic attacks in phobic patients.

Some of the older antidepressants such as Desipramine and Maprotiline, as well as some of the newer ones such as Duloxetine and Atomoxetine, work on the norepinephric system. Substances used and abused to keep anxiety under control, such as alcohol, opiates, and benzodiazepines, all decrease the firing of noradrenergic neurons and thus reduce anxiety.


The HPA Axis and its end-product Cortisol, are also involved in reactions to stress. This is the emergency response team for stress. The HPA axis is actually a feedback loop in which the hypothalamus produces corticotrophin – releasing hormone that pushes the pituitary to produce ACTH (adrenocorticotropic hormone) that stimulates the adrenal glands to produce Cortisol – the stress hormone. Cortisol has an inhibitory feedback effect on the pituitary, thus keeping the system in check.

This system contributes to adaptation in acute stress responses and helps the organism to cope by increasing alertness and arousal. However, sustained and excessive Cortisol secretion can lead to serious adverse effects, including hypertension, immune suppression, insulin resistance, and even cardiovascular disease. These effects are most noticeable in people experiencing continuous long-term stress such as those suffering from post-traumatic stress disorder.


The benzo-GABA system represents the brakes in the system. It lowers the level of anxiety. This system is best known through its association with Valium (diazepam) and Librium (chlordiazepoxide), the earliest forms of benzo-diazepine medications (known then as tranquilizers). Currently, Clonazepam (Klonepin or Rivotril) and alprazolam (Xanx) are the most commonly used in psychiatry. In general medicine, lorazepam (Ativan) is frequently administered and is a favorite with emergency room physicians since it is available in injectable and sublingual forms.

Benzodiazepine recognition sites are located on the aminobutyric acid (GABA) type A receptors in the central nervous system. Activation of benzodiazepine-GABA receptor complexes also suppresses the HPA axis previously described as the basis of the stress response.


The serotonin neurotransmitter system is best known for its role in depression. Serotonergic drugs such as Prozac, Paxil, and Zoloft have become the mainstays of anti-depressant treatment. However, they have also proved effective in a variety of anxiety disorders including Panic Disorder, ObsessiveCompulsive Disorder and Post-Traumatic Stress Disorder.

Serotonin may increase or decrease anxiety. It is a bimodal system in this sense. It may have anxiogenic (causing anxiety) effects via the 5HT 2A receptor or anxiolytic effects (reducing anxiety) via the 5 HT 1 A receptor. As well, there are important interconnections between the HPA axis, mentioned previously, and the benzodiazepine-GABA system. Each system interacts with the others in complex and synergistic ways.

We begin to see here how complex the anxiety process can be from a neuro-chemical point of view. This has clinical relevance since serotonin, which has considerable efficacy in reducing anxiety may also increase it in the early stages of treatment. The agitation thus produced may actually lead to suicidality or to the Serotonergic Syndrome if this system gets over-amped. Here, the result may be a sweaty, tremulous, or even delirious patient because of the excess of serotonin a serious clinical situation indeed.

As we can see the neurochemical system is complex and interactive. No system works on its own. A change in the serotonergic system may well cause a change in the GABAergic system and vice-versa. Among the consequences of this are side effects, a problem that one has to constantly monitor in the use of medications. This, however, does not mean that medications are universally harmful. What it does imply is a regular cost-benefit analysis in the use of medications. For example, if one uses an anti-depressant medication and observes an increase in liver enzyme levels (which is, fortunately, not very frequent), one must monitor the situation closely. There is no point in curing a depression while causing a worse problem of liver damage.

As an interesting aside, the problem of side effects is not restricted to the field of medicine. Every human intervention has the possibility of causing adverse effects. While pursuing my interests in buildings and their relationship to health, I met a very clever building inspector. He told me that the majority of times he had been called to deal with building-related issues, the problem, in fact, had been the solution to a previous problem. A fertile matter to reflect upon!


Much of the study of anxiety has centered on the amygdala (an almond-shaped structure attached to the cerebellum) and its lateral and central nuclei. Functional imaging studies (PET scans and functional MRIs) have demonstrated increased hemodynamic activity in the amygdala during exposure to fear-inducing stimuli. As in most biological processes that have been studied, this mechanism involves considerably more than one simple structure. We need to think more in terms of circuits than about single entities. Other related structures include the perirhinal cortex, the ventral lateral prefrontal cortex (VLPFC), and the anterior insula.

The medial temporal lobe system, related to memory, also has extensive anatomical connections to the amygdala. What this implies is that our cognitions (from the pre-frontal cortex) and our memory (from the medial temporal lobes) are intensely involved in our perception of fear. None of this should be surprising to the observant individual.

Another structure thought to be specifically involved in anxiety, as opposed to fear, is the bed nucleus of the striaterminalis. This area has a similar neuro-transmitter content to that of the amygdala as well as similar hypothalamic and brain stem connections.

I realize that this description is difficult to follow without an atlas of neuro-anatomy or sufficient training in this area. What is important to realize here (the take-home message if you wish) is that the biological basis of anxiety is very complex indeed, and the more it is studied the more complex it becomes. The experience of anxiety, however, is very simple and compelling when one has to deal with it. Such are the limitations of objective science. Because of this complexity’, our biological treatments turn out to be quite non-specific. Nevertheless, they are quite effective and often unavoidable. ?

PART TWO will be published in Issue 18.

NB : The details of the case histories in this article have been altered to protect the identities of the persons involved. Any resemblance to persons alive or deceased is only very partial and neither their identities nor the characteristics of their lives should be inferred.

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