Brain Chemistry Basics

You've probably probably heard the term "neurotransmitter" before,  but what does this really mean?  Neurotransmitters are chemical messengers within the brain that facilitate communication between nerve cells.  Let's illustrate with serotonin.  Figure 1 depicts the junction between two nerve cells.  Packets of serotonin molecules are released from the end of the presynaptic cell (the axon)  into the space between the two nerve cells (the synapse).  These molecules may then be taken up by serotonin receptors of the postsynaptic nerve cell (the dendrite) and thus pass along their chemical message.  Excess molecules are taken back up by the presynaptic cell and reprocessed.

Several things might potentially go wrong with this process and lead to a serotonin deficit.  Just to enumerate a few possibilities:

• Not enough serotonin is produced,

•  There are not enough receptor sites to receive  serotonin,

• Serotonin is being taken back up too quickly before it can reach receptor sites, 

• Chemical precursors to serotonin (molecules that serotonin is manufactured from) may be in short supply, or

• Molecules that facilitate the production of serotonin may be in too short supply.

As you can see, if there is a breakdown anywhere along the path, neurotransmitter supplies may not be adequate for your brain's needs.  Inadequate supplies lead to the symptoms that we know as depression.

The Primary Players

There are three basic molecules, known  chemically as monoamines, which are thought to play a role in mood regulation:   norepinephrine, serotonin and dopamine. 

In the 1960s Joseph J. Schildkraut of Harvard University cast his vote with norepinephrine as the causative factor for depression in the now classic "catecholamine" hypothesis of mood disorders. He proposed that depression stems from a deficiency of norepinephrine  in certain brain circuits and that mania arises from an overabundance of this substance.¹  There is indeed a large body of evidence²  that supports this hypothesis, however, changes in norepinephrine levels do not affect mood in everyone.  The implication is that medications such as reboxetine, which specifically targets norepinephrine, will work for some persons but not others.³  

Obviously there must be some other factor that interacts with norepinephrine to cause depression.  Serotonin has been found to be this other factor.  This molecule has taken center stage in the past two decades thanks to Prozac and other Selective Serotonin Reuptake Inhibitors (SSRI's), which selectively act on this molecule.  Serious investigations into serotonin's role in mood disorders, however, have been going on for almost 30 years, ever since Arthur J. Prange, Jr., of the University of North Carolina at Chapel Hill, Alec Coppen of the Medical Research Council in England and their co-workers put forward the so-called "permissive hypothesis". This view held that synaptic depletion of serotonin was another cause of depression, one that worked by promoting, or "permitting," a fall in norepinephrine levels.  So, although, norepinephrine still played a major role in depression, serotonin levels could be manipulated to indirectly raise norepinephrine.  Newer antidepressants like Effexor are actually targeted at both serotonin and norepinephrine.⁴  Tricyclics (TCAs) also affect both norepinephrine and serotonin, however, they have the added effect of influencing histamine and acetylcholine, which produces the side-effects that TCAs are known for, such as dry mouth or eyes, peculiar taste in mouth, sensitivity to light of the eyes, blurry vision, constipation, uninary hesitancy, and others.  SSRIs do not affect histamine and acetylcholine and thus do not have the same side-effects as the older medications.⁵

A third substance that may play a role in mood is dopamine.  Dopamine is associated with the reward, or reinforcement, that we get which causes us to continue participating in an activity.   It has been implicated in such conditions as Parkinson's Disease and schizophrenia.  There is also some evidence that, at least for a subset of patients, dopamine plays a role in depression.⁶  Dopaminergic substances and stimulants have been used as antidepressants when other measures have failed.⁷  Some studies have investigated dopaminergic agents as a rapid method of relieving depression (in contrast to medications which may take up to six weeks to exhibit their full effect).⁸  

Although agents that work selectively on dopamine have the benefit of fast action, they have also exhibited some properties which have kept them from being as widely used as other antidepressants.  Dopamine is a neurotransmitter that is associated with addiction and it's production is stimulated by drugs such as cocaine, opiates and alcohol (which may explain why depressed persons choose to self-medicate with drugs and alcohol.⁹⁾  Drug specifically targeted at dopamine, for example amineptine (Survector), present the potential for abuse.¹⁰   For this reason, amineptine is not approved for use in the US or Britain at this time.

All Depressed Brains Are Not the Same

Very often I am asked to recommend a good antidepressant.  My answer, other than the obvious, "Please see your doctor for medical advice", is this: "the one that works for you"!  

Each class of antidepressant works on your brain chemistry in a different way.  Dr. Abbott Lee Granoff, a noted expert in the field of panic disorder and depression, says the following:  "There are currently 23 antidepressants on the market (Guide Note:  this figure is for the US only.  There are some antidepressants available in other countries which are not approved for use in the US). Each increases certain neurotransmitters in the brain and each can do this in slightly different parts of the brain."¹  So, while one person may get relief from having their serotonin boosted, another may need a drug that affects both serotonin and norepinephrine. Still another person may need an entirely different sort of medication, such an anticonvulsant or a mood stabilizer like lithium.   Further, a person who does well on a medication such as Zoloft may not do as well on Prozac, even though both belong to the same class.²  Each person will be very different in their medication needs.

Just like the wide variety of brains, there are a wide variety of antidepressants.  Broadly speaking, these fall into the following classes:  monoamine oxidase inhibitors (MAOIs), tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs).  There are also several newer medications that are unique in their mechanism of action.

Monoamine Oxidase Inhibitors

The monoamine oxidase inhibitors (MAOIs) were some of the first antidepressant medications developed.  The neurotransmitters responsible for mood, primarily norepinephrine and serotonin, are also known as monoamines.  Monoamine oxidase is an enzyme which breaks these substances down.  Monoamine oxidase inhibitors, as the name implies, inhibits this enzyme, thus allowing a greater supply of these chemicals to remain available.

MAOIs have fallen out of favor as first-line antidepressants because they offer several disadvantages to patients compared to newer medications.  Potentially fatal drug-drug interactions can occur with MAOIs when combined with a variety of drugs which are serotonin agonists (the "serotonin syndrome") or norepinephrine agonists.³    People on these medications must also follow strict dietary restrictions of foods rich in tyramine⁴ to avoid potential hypertensive (high blood pressure) crisis.  A major adverse effect that occurs on MAOIs alone is hypotension (low blood pressure), which can present as fatigue and may mimic worsening of the underlying depressive syndrome. For this reason, the blood pressure should always be monitored when using these antidepressants.⁵  

Tricyclics

Tricyclics, also known as heterocyclics, came into broad use in the 1950's.  These drugs inhibit the nerve cell's ability to reuptake serotonin and norepinephrine, thus allowing a greater amount of these two substances to be available for use by nerve cells.

In addition to acting on norepinephrine and serotonin, tricyclics exhibit similar effects on histamine and acetylcholine.  This is responsible for the troublesome side-effects we usually associate with these medications, such as dry mouth, blurry vision, weight gain and sedation.⁶ 

With tricyclics, a patient's medical history must be closely considered.  These medications may cause orthostatic hypotension (dizziness upon standing); rapid heartbeat, sometimes with palpitations; and may aggravate preexisting heart conditions.  Patients with a history of seizures or head injury must also be cautious as these drugs may cause seizure.⁷

Selective Serotonin Reuptake Inhibitors

Claims of decreased side-effects and increased safety relative to the older medications have made this class of antidepressant very popular in recent years.  Five drugs currently belong to this class:  fluoxetine (Prozac), citalopram (Celexa), fluvoxamine (Luvox), sertraline (Zoloft), and paroxetine (Paxil).

SSRI stands for Selective Serotonin Reuptake Inhibitor.  These medications work, as the name implies, by blocking the presynaptic serotonin transporter receptor.⁸   This drug differs from the tricyclics in that it's action is specific to serotonin only.  It's effect on norepinephrine is indirect, through the fact that falling serotonin "permits" norepinephrine to fall so preserving serotonin preserves norepinephrine.⁹     

SSRIs, through their specificity, have the advantage of not affecting histamine and acetylcholine.  The implication is that although they are not without side-effects, they do not create the same bothersome side-effects as the tricyclics.

Newer Mechanisms

Five newer medications which do not fit into the above categories are:  buproprion (Wellbutrin), nefazodone (Serzone), trazodone (Desyrel), venlafaxine (Effexor), and mirtazapine (Remeron).  

The mechanism of bupropion's antidepressant activity is poorly understood, but is thought to be mediated through noradrenergic or dopaminergic pathways or both.¹⁰ This medication lacks the sexual side-effects so common to the SSRIs and is popular for patients who exhibit a lack of energy, psychomotor slowness and excessive sleep.

Nefazodone and  it's precursor trazodone both inhibit neuronal reuptake of serotonin and, to a lesser extent, norepinepherine. They also blocks postsynaptic 5-HT₂ receptors. Nefazodone has weak affinity for cholinergic and a₁- adrenergic receptors and, therefore, is associated with less sedation and orthostasis than trazodone.¹¹

Venlafaxine is a compound that is structurally unrelated to other antidepressants.¹² Like the TCAs, venlafaxine inhibits the neuronal uptake of both serotonin and norepinepherine.  Venlafaxine has dose-dependent, sequential effects on the uptake pumps for serotonin and then norepinephrine.. At 75 mg/day, venlafaxine is predominantly a serotonin reuptake inhibitor (SRI) like the SSRIs. At 375 mg/day, it produces comparable norepinephrine uptake inhibition to an NSRI such as desipramine.¹³

Mirtazapine is the most recently released of these four and is the first a₂-antagonist marketed as an antidepressant.¹⁴ Mirtazapine's unique mechanism of action does not involve enzyme inhibition or blockade of neurotransmitter reuptake. Mirtazapine increases the release of norepinepherine from central noradrenergic neurons by blocking the presynaptic inhibitory alpha-2 autoreceptors. It spares the alpha-1 postsynaptic receptor and therefore results in net increase noradrenergic transmission. As a second presynaptic receptor blocking function, mirtazapine blocks the inhibitory alpha-2 heteroreceptors located on serotonergic neurons, resulting in increase release of serotonin. Postsynaptically, mirtazapine has low affinity for the 5-HT1A receptor, thus allowing serotonin released into the synapse to bind to and stimulate this receptor. However, it blocks postsynaptic 5-HT2 and 5-HT3 receptors. Stimulation of the 5-HT2 receptor is thought to be responsible for the serotonergic side effects of insomnia, agitation, and sexual dysfunction seen with the SSRI's and 5-HT3 receptor stimulation is thought to mediate nausea seen with these agents.^{15, 16, 17} Therefore, mirtazapine's receptor blocking profile prevents the side-effects seen with nonselective activation of serotonin receptors which occurs with pure reuptake blockers.

A Method to the Madness?

The selection of an antidepressant is not nearly so "hit or miss" as it might feel.  There is a definite logic behind the sequence of antidepressants that a doctor proceeds to try as he/she seeks the one for you.  One tool available to help in selection is what's called an "algorithm", which is a flow chart that provides the best antidepressant selection based upon the answers provided to certain questions.  These selections are based upon current knowledge in the field of psychiatry about what antidepressant is best for which type of depression. 

The Patient's Say

Just as important as whether a drug relieves depression is how good a fit a drug is for the individual.  A patient may find that a particular drug makes them feel the best they have in years, but the side-effects are intolerable.  What happens now?  This is the point when physician and patient must work as a team to find a solution that the patient can live with.  Options might include accepting the side-effect as a trade off for depression relief, augmenting with other medications, or trying a new medication.  The important thing is for the patient to be open about their expectations, but also realistic.  One should try to find the drug which gives the best depression relief with the fewest side-effects, but keep in mind that no drug is going to be perfect.  

Worst Offenders List

There are two side-effects that people seem to find the most troubling:  sexual dysfunction and weight gain.

One of the classic symptoms of depression is loss of sex drive.  Rather ironically, just about all medications used to treat depression can also potentially cause sexual side-effects.  If these problems affect you, Serzone, Wellbutrin and Remeron are medications which have fewer sexual side-effects.

Weight gain is another commonly complained about side-effect.  In this department, Paxil and Remeron are the worst offenders.  Effexor, Wellbutrin, and Prozac do not seem to cause weight gain as badly, and may even cause patients to lose a few pounds.

Side-Effects Can Be a Good Thing

Believe it or not, side-effects are not necessarily a bad thing.  They can be good or bad, depending upon other illnesses or conditions that the patient has.  If a patient has an eating disorder, a drug like Prozac that suppresses appetite may not be desirable.  However, if a patient is diabetic, this same side-effect may be helpful in controlling their diabetes because they will have fewer cravings for forbidden foods.  Conversely, if you need to put on some weight, Paxil or Remeron might be the best antidepressants to use.

Pulling Double Duty

Certain antidepressants have been found to be effective for conditions other than depression.  If you have another condition along with depression that might be benefited by a particular antidepressant, a doctor may opt to try that medication..  Wellbutrin is actually the same drug as Zyban, the popular stop-smoking medication.  For a smoker, Wellbutrin might be a logical choice.  Do you also suffer from Obsessive Compulsive Disorder?  Try an SSRI.  Are you painfully shy?  Paxil may be a good choice.  Do you suffer from PMS?  Zoloft or Prozac may be for you.

A Complex Problem

If you've read the other installments in this series or you've struggled to find a medication that helps you, then you already know the treatment of mood disorders is not a simple matter.  It is not so simple as diagnosing depression and writing a prescription for Prozac.  The individual causes of depression are diverse and poorly understood.  The medications used to treat it are just as diverse and matching a drug with an individual is not a clear cut decision.  Individual symptoms, co-existing illness, tolerance of side-effects, and other medications previously tried are just a few factors that must be considered.  Then there are the difficulties in making an exact diagnosis.  Bipolar disorder in particular may be misdiagnosed, especially if patients "fall on the edge" of DSM-V criteria.¹  Symptoms of mania may be overlooked by the patient because depressive symptoms are the ones that feel so bad and first bring a patient in for help. Symptoms of bipolar disorder may also be confused with other disorders.^2,3,4  Further add to this mix the fact that there are no brain scans or blood tests one can take to make a definitive diagnosis.⁵  Doctors must rely on a set of signs and symptoms as well as the patient's history.  Diagnosing and treating depression and manic depression is not a simple matter at all!

When one realizes the complexity of this issue, it becomes easy to see that treating mood disorders is not an exact science.  Rather it is an art form requiring a combination of patience, knowledge, judgment, willingness to experiment with new treatments, the ability to network with one's peers and a desire to keep up with current medical journals and developments in the field.  Now, compare that with the fact that most people first seek help for their mental health problems through their family physician,⁶ a doctor who does not specialize in these conditions, but rather must be a "jack of all trades" treating and screening for a wide range of illnesses.  Your family doctor simply does not have the time or energy needed to keep up with the specialized knowledge necessary to treat mood disorders. 

What Your Doctor Doesn't Know Can Hurt

Studies show that 74% of people seeking help for depression will first go to their primary care physician. Of these cases, as many as 50% are misdiagnosed. Even of the cases that are correctly diagnosed, 80% are given too little medication for too short a time.⁷  Considering that depression can have the fatal outcome of suicide if not properly treated, these are some sobering statistics.

Of course, some people will do just fine with their primary care physician.  They will get a proper diagnosis and may even be fortunate enough to be responders to the first medication that their physician prescribes (usually an SSRI or one of the newer medications).  This, however, may be more luck than skill since it is estimated that between 60%-80% of patients will respond to any particular medication.⁸  

What if you are not one of the lucky? What if you are treatment resistant?  What if you do well for a few months and then your medication stops working?  What if you can't tolerate the side-effects?  It won't take long to see that your doctor is floundering.  He or she may not know what to try next.  Meanwhile, you have spent quite a bit of time and money seeing a doctor who is not adequately trained to treat your condition.  Your doctor's inexperience at minimum may lead to frustration and added expense.  At worst it can be a prescription for disaster.  Why risk it?

Who's an Expert?

So, whom should you see to ensure that you are in the hands of an expert?  Although there is some controversy over whether therapy, drugs or a combination of both are best for depression, there is really one type of doctor who is qualified to treat depression and other mood disorders using medications:  a psychiatrist.  A psychologist, also qualified to treat depression, is not a medical doctor and therefore cannot prescribe drugs.  A psychologist specializes in talk therapy.  If you are uncertain whether you need medications, it is best to begin your treatment under the care of a psychiatrist.  If you will also benefit from talk therapy, psychiatrists are generally able to handle this as well, although some may elect to refer you to another therapist. There is a wide gap in knowledge that can only be filled by experience, especially in more difficult to treat patients.  Choosing a psychiatrist over a primary care physician is no guarantee of experience, but it does improve your odds considerably.

The Primary Care Physicians's Important Role

Keep in mind that you should not skip your primary care provider altogether.  In fact, depending upon your insurance coverage, you may have to see him/her in order to get a referral.  Your primary care provider does play a very important role, both in screening you for possible mood disorders and in screening for other illnesses that may mimic depression symptoms (such as hypothyroid, nutrient deficiencies, and drug reactions).  Once it is determined that you are healthy and may possibly have a mood disorder, however, your doctor should make you a referral to a specialist who is qualified to make a diagnosis and treat you.  If your doctor does not offer to make this referral, insist upon it.  After all, you are paying your doctor for a service.  You have the right to expect care from a qualified expert. 

Better Diagnostic Tools

Currently mood disorders are diagnosed based upon a patient's symptoms and history, but what if we could perform an actual lab test that would detect depression?  This very thing may be available in the future.

Magnetic resonance imaging (MRI) and other imaging tools that assess brain structure have produced several provocative findings.  Views of the subcortical white matter in manic-depressive (bipolar) patients, especially elderly ones, reveal an unexpectedly high number of bright spots in certain brain regions known to be involved in mood (such as the basal ganglia, thalamus and brain stem).  Also, the volume of various brain structures is reduced in long-term sufferers of depression. Among these is the hippocampus, a part of the limbic system (involved in emotion and memory).  This finding is consistent with animal data suggesting that chronic oversecretion of cortisol, as occurs in many depressed individuals, can destroy hippocampal cells.¹  

Positron emission tomography (PET) has shown that patients with major depression compared with normal persons show different patterns of activity in several limbic and cortical brain areas.  In addition, one PET analysis revealed that increased activity in a region of the limbic system--the amygdala of the left hemisphere--might be an indicator of heightened vulnerability to future depression.²  

Functional imaging technology can also be used to examine the concentrations of neurotransmitters, so that densities of those molecules can be compared in different people and in various areas of the brain. Traceable substances that bind to the serotonin reuptake transporter (which removes serotonin from synapses) and to one type of serotonin receptor have now been developed and should provide valuable information about exactly which brain areas show depleted serotonin activity in depressed patients.³

Although scientists do not fully understand the implications of these finding and how they might be used to develop a definitive test for mood disorders, it seems it may only a matter of time before depression diagnosis goes high tech.

A Pacemaker for the Brain

Research is increasingly showing a compelling link between depression and epilepsy.  A recent study found that older adults who are clinically depressed are six times as likely to have a seizure as their peers, suggesting that a common factor may be the cause of both depression and seizures.⁴  

Not surprisingly, some individuals who have not responded to antidepressant therapy do respond to anticonvulsant medications such as Lamotrigine (Lamictal)⁵, Gabapentin (Neurontin)⁶, and Topiramate (Topamax)⁷.  These medications are currently only approved for people who have seizures, but there are many case reports supporting their use for treatment resistant mood disorders.

Following this link to it's logical next step, researchers have begun to investigate the use of an epilepsy treatment called Vagus Nerve Stimulation (VNS) as a treatment for depression.  Results of the VNS pilot study showed that 40% of the treated patients displayed at least a 50 percent or greater improvement in their condition, according to the Hamilton Rating Scale for Depression.  Half the patients also had at least a 50% improvement on the Montgomery Asberg Depression Rating Scale. The condition of several patients improved so substantially that they were able to return to work or other normal activities.⁸

The device used for this therapy (currently only approved for epilepsy treatment), the NeuroCybernetic Prosthesis System (NCP), is often referred to as a "pacemaker for the brain".  The system consists of a pulse generator and a nerve stimulator electrode that is usually programmed to send 30-second electrical impulses every 5 minutes to the left vagus nerve, via connecting leads. The generator is surgically placed in a pocket formed under the skin, below the left collarbone. It's disc shaped and about the size of an baby's palm.  It is similar in appearance and size to a cardiac pacemaker. The surgery takes about forty-five minutes, and is considered a safe procedure with very little risk. The generator's "dosage of stimulation" is adjusted non-invasively through the skin using a computerized programmer.⁹

Magnet Therapy

A new therapy showing great promise for replacing Electroconvulsive Therapy (ECT) is Transcranial Magnetic Stimulation. (TMS).  It appears to affect the brain in a similar way to ECT, but without the need for anesthesia or side-effects such as memory loss and any risks associated with seizure and general anesthesia.. In the pilot rTMS (repetitive Transcranial Magnetic Stimulation) study, the only reported side effects were that two patients developed mild headaches, treatable with aspirin.¹⁰

TMS involves passing current through an electromagnetic coil to generate a magnetic field.  The magnetic field acts as the medium between electricity in the coil and induced electrical currents in the brain. The current depolarizes neurons in the brain up to a depth of about two centimeters below the brain's surface.  It does not requires any sort of anesthesia or analgesics.¹¹  This treatment is under investigation in several locations all over the world.¹²

Medications

Perhaps the area where the most immediate results will be seen is in the area of new medications that have novel modes of action.  

A medication that has already made an appearance in Europe and will soon be available here in the US is Reboxetine (brand name Vestra or Edronax).  Reboxetine is a unique approach to depression treatment in that it targets the neurotransmitter norepinephrine.  No other drug on the market can make that claim.  It is hypothesized that up to 20% of depressed persons have a shortage of this chemical, 20% have depression related to serotonin, and the other 60% are mixed.  This means that a whole new avenue of treatment is opening up to address a mechanism of depression causation that was not addressed before.¹³

Another promising drug is one that blocks the "substance P" protein, which Merck and Co. bills as the most exciting product in it's pipeline.  The first drug researched that targeted this substance was a compound called MK-869.  In 1998 scientists from Merck & Co. announced in the journal Science that in pre-clinical trials their new compound had the same rate of efficacy in relieving depressive symptoms as other currently available drugs. These results were somewhat surprising because the target of its action was neither norepinephrine nor serotonin, but the neuromodulator, substance P. It was speculated that the drug acts by blocking the substance P receptors that are localized in neural pathways involved in negative emotions.¹⁴   Merck has since dropped studies on MK-869, but is studying a second generation Substance P blocking drug.  In June of the current year it was announced that patient enrollment is taking longer than expected for studies involving this new drug and it is uncertain at this point when or if this new drug will ever become available.  It is, however,  projected that the Phase II study will be completed in the first quarter of 2001.¹⁵

In Conclusion

The most important message to be taken away from this series of articles?  Don't give up hope.  Each day we are learning more and more about what causes depression and how to treat it more effectively.  Even if you feel like you've exhausted all your options, there may be some new development in the works that will help you.  Or a treatment that's already available that you don't know about.  So keep reading and researching and learning everything you can.  Recovery from depression is attainable and so very worthwhile.