Which type of drug usually works by decreasing activity at the dopamine receptors in the brain?

As the brain continues to adapt to the presence of the drug, regions outside of the reward pathway are also affected. Over time, brain regions responsible for judgment, decision-making, learning, and memory begin to physically change, making certain behaviors “hard-wired.” In some brain regions, connections between neurons are pruned back. In others, neurons form more connections.

Once these changes take place, drug-seeking behavior becomes driven by habit, almost reflex. The drug user becomes a drug addict.

After cocaine use, connections between neurons in the nucleus accumbens, part of the reward pathway, increase in number, size, and strength.

Reprinted from the "Medications" issue of Visions Journal, 2007, 4 (2), pp. 7-8

Depression and schizophrenia are two of the many mental illnesses that a physician can treat with effective medications. Knowing how medications work can increase your understanding of mental illness and encourage compliance—that is, consistently sticking to your medication treatment plan so that the medications are given a chance to be effective. This article will explain how antidepressant and antipsychotic medications work in the brain to treat these disorders.

How our brains work

The central nervous system (CNS), made up of the brain and spinal cord, controls our actions, thoughts and emotions. These functions are controlled by chemicals called neurotransmitters.† Neurotransmitters travel between different regions of the brain via nerve cells called neurons.

There are several different neurotransmitters that act on parts of these nerve cells called receptors. This produces effects that can influence memory, emotion, voluntary movement of muscles, appetite, temperature regulation and more. Figure 1 shows how this process works.

Figure 1: How neurotransmitters work between nerve cells

What is depression?

Although the exact cause of depression is not known, biological, genetic and environmental factors are thought to play a role. Depression is often associated with various conditions including emotional upset (e.g., divorce, death in the family, major financial problems), co-existing medical conditions (e.g., stroke, heart attack, cancer), hormonal disorders (e.g., underactive thyroid, menopause) and problem substance use (i.e., alcohol and other drugs). Depression also often co-occurs with other mental illnesses, including bipolar disorder, schizophrenia and anxiety disorders.

Whatever the trigger, it is believed that the underlying biological basis of depression is a depletion in the levels of neurotransmitters such as serotonin, norepinephrine, and/or dopamine in the central nervous system.

Antidepressants
All antidepressants† work in a similar way, though there are various types of antidepressants—often called “families”—that each work a bit differently. They all, however, increase the brain’s concentration of various neurotransmitters.

One of the older antidepressant families, tricyclic antidepressants (TCAs), increase both norepinephrine and serotonin concentrations, generally speaking. However, some TCAs will increase serotonin concentrations more than they increase norepinephrine (e.g., clomipramine), and others increase norepinephrine concentrations more than serotonin concentrations (e.g., nortriptyline and desipramine).

Monoamine oxidase inhibitor antidepressants (MAOIs) comprise another family. It includes medicines like phenelzine, isocarboxazid and moclobemide. MAOIs work by stopping the breakdown of monoamine neurotransmitters, which helps keep the brain’s concentration of neurotransmitters at levels that help improve mood.

Side effects often associated with TCAs and MAOIs include drowsiness, weight gain, dry mouth, constipation, blurred vision, dizziness and sexual dysfunction. Because of these side effects, doctors will usually prescribe a newer antidepressant first.

These older drugs remain on the market because, in some people, newer medications don’t work as well as the older medications.

Newer antidepressants act in a similar way to treat depression, with the advantage of fewer side effects. The most commonly prescribed group of antidepressants is selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, paroxetine, fluvoxamine, sertraline and citalopram. The main action of SSRIs is to increase the concentration of serotonin.

The antidepressant venlafaxine is described as a serotonin norepinephrine reuptake inhibitor (SNRI); it increases serotonin and norepinephrine concentrations. At higher doses, venlafaxine also increases dopamine concentrations.

If an antidepressant increases serotonin concentrations, side effects can include nausea, changes in appetite and sexual dysfunction.

Bupropion is an antidepressant that doesn’t increase serotonin concentrations, but does increase levels of norepinephrine and dopamine.

Lastly, the anti­depressant mirtazapine enhances neurotransmission by increasing the concentrations of both serotonin and norepinephrine. Unlike the SSRIs, mirtazapine blocks specific serotonin receptors, reducing the potential to cause side effects such as sexual dysfunction and nausea.

Anti­depressants are often very effective; however, it is important to realize that it takes time for them to take effect. Some people suffering from depression may notice an improvement in symptoms after two weeks of treatment. But, most people will require at least four to eight weeks of treatment before noticing a positive response. Unfortunately, side effects usually appear before the benefits of antidepressant medications are recognized. Discussing these side effects with your doctor or pharmacist may provide you with a better understanding of what is happening and how to manage it.

As a side note: antidepressants are prescribed to treat and manage other illnesses. TCAs, for example, have local anesthetic-type properties and have been used to treat chronic pain due to nerve injury. SSRIs, on the other hand, are commonly prescribed to treat various anxiety disorders that share a common underlying cause involving serotonin.

What is schizophrenia?

Schizophrenia is a chronic psychotic disorder with onset typically occurring in late adolescence or young adulthood. The symptoms of schizophrenia can be divided into positive† and negative† symptoms. Positive symptoms can be described as an excess or distortion of normal functions, such as hallucinations, delusions and thought disorders. Negative symptoms can be described as a reduction or loss of functions; they include slowed thoughts or speech, loss of expressed emotions, lack of motivation, attention deficits and loss of social interest.

Schizophrenia is associated with an increase in dopamine activity in an area of the central nervous system called the meso­limbic pathway. The meso­limbic pathway is one of four major dopamine-related pathways in the brain that is associated with pleasurable feelings, with addiction—and with psychosis.

Antipsychotics
Generally speaking, anti­psychotic medications work by blocking a specific subtype of the dopamine receptor, referred to as the D2 receptor. Older antipsychotics, known as conventional antipsychotics, block the D2 receptor and improve positive symptoms. Unfortunately, these conventional antipsychotics also block D2 receptors in areas outside of the mesolimbic pathway. This can result in a worsening of the negative symptoms associated with the illness. Conventional antipsychotic medications include chlorpromazine, haloperidol, trifluoperazine, perphenazine and fluphenazine.

A second generation of antipsychotics, commonly referred to as the atypical antipsychotics, block D2 receptors as well as a specific subtype of serotonin receptor, the 5HT2A receptor. It is believed that this combined action at D2 and 5HT2A receptors treats both the positive and the negative symptoms. The atypical anti­psychotics currently available in Canada include clozapine, risperidone, olanzapine, quetiapine, paliperidone and ziprasidone.

Like all medications, antipsychotics have side effects. Side effects from blocking the D2 receptor can include tremors, inner restlessness, muscle spasms, sexual dysfunction and, in rare cases, tardive dyskinesia, a disorder that causes repetitive, involuntary, purposeless movements. These side effects are more often associated with the older conventional anti­psychotics—which, again, may still work better for some people—but that is not to say that atypical medications don’t have side effects. Side effects associated with the atypical antipsychotics include weight gain, diabetes and lipid disorders. These side effects are more often associated with clozapine and olanzapine.

Note that antipsychotic agents are also prescribed to treat other conditions apart from schizophrenia. This is referred to as “off-label”† prescribing and includes conditions such as Tourette’s syndrome, substance abuse (e.g., cocaine and methamphetamine), stuttering, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder and personality disorders.

It is important to keep in mind that, like anti­depressants, anti­psychotic medications do not work immediately; it may take up to eight weeks to see the therapeutic benefits. And the side effects tend to occur before improvement in the symptoms of the illness is experienced. However, anyone experiencing troublesome side effects should consult their doctor or pharmacist.

To conclude

Clearly, depression and schizophrenia are very complex and debilitating disorders. Fortunately, medications like anti­depressants and anti­psychotics can help treat the core symptoms. Knowing how these drugs work and what effects they can have will be an important step in using them properly and effectively.

About the authors

Anthony graduated from UBC in Pharmacy in 2006. He is currently a pharmacy resident with Fraser Health.

Ric is a Clinical Research Psychopharmacologist at Riverview Hospital, and a Clinical Associate Professor in Pharmaceutical Sciences and in Psychiatry at UBC. His research interests include  smoking and schizophrenia, antipsychotic polypharmacy and drug utilization evaluations. Ric has received seven teaching awards from UBC’s Faculty of Pharmaceutical Sciences.

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