Psychopharmacology: Medications for the Mind

The family of medications known as the benzodiazepines is the heart of anxiolytic, or antianxiety treatment. Benzodiazepines are not a cure for anxiety. Their purpose is that of short-term, symptomatic, adjunctive treatment while other lasting solutions are sought for the core issues creating the anxiety.

The recent development of new medications, which seem to act on brain benzodiazepine receptor sites without being true benzodiazepine chemicals opens another path of future treatment of anxiety. The FDA currently approves three benzodiazepine-related medications (zolpidem, zaleplon, eszopiclone) for the treatment of insomnia.

Buspirone (Buspar) is a dopamine (D2 receptor) blocking medication approved for use by the FDA for the treatment of generalized anxiety disorder. Structurally different from the benzodiazepines, buspirone can be used for long periods with no potential for abuse, dependence, or tolerance.⁶ What buspirone lacks is the quick onset associated with many of the other antianxiety medications. Several weeks of daily dosing is required to achieve anxiolytic benefits.

Gamma-aminobutyric acid (GABA) is a key neurotransmitter associated with anxiety. Medications such as the benzodiazepines (e.g. Valium, Ativan, etc.) and the barbiturates interact with the availability or reception of GABA in the central nervous system. Benzodiazepine medications bind to neurotransmitter receptor sites BZ1 and BZ2 (benzodiazepine receptor sites 1, and 2) and potentiate the effects of GABA. BZ1 is thought to be closely associated with sleep function, while BZ2 influences cognitive, sensory, motor and memory abilities.

In general, benzodiazepines are considered equally effective. Drug choice should be based on individual concerns such as how long it takes to reach effect and how long the effect is desired.

Pharmacologic agents that affect the brain chemistry in such a way as to lifts mood or diminish the symptoms of depression are known by the term antidepressant. Clinical depression is widely believed to be the result of a functional imbalance in the endogenous neurotransmitters of the brain associated with mood (e.g. serotonin, dopamine, and norepinephrine).

The reasons for such imbalance may be on the supply side (i.e. not enough of the correct neurotransmitter is being made), or it may originate on the receiving side (not enough specific receptor sites are available). There may be some unanticipated factor interfering with the function of the neurochemical message system such as malformation of the neurotransmitter molecule, blockage by a third-party neurochemical or pseudo-neurochemical, etc. In most instances, the exact cause is never known, creating the neurohormonal imbalance which results in a given individual's depression. What is known is that when one antidepressive agent fails, there are options that include antidepressants that work by different mechanisms.

Several classes of antidepressant medication exist, grouped together by the neurotransmitter(s) they primarily affect. Antidepressant groupings include;

• Monoamine Oxidase Inhibitors
• Norepinephrine-Dopamine Reuptake Inhibitor
• Selective Serotonin Reuptake Inhibitors
• Serotonin Dopamine Activity Modulators
• Serotonin Modulators
• Serotonin Norepinephrine Reuptake Inhibitor
• Tricyclic Agents

Antidepressants do not work overnight and may not work at all. In a large study by the British Royal College of Psychiatrists, those clients on antidepressants for three months showed only 50 to 60 percent reporting significant improvement.8 Other studies have shown that around half of clients prescribed antidepressants have no true benefit and many who do have a therapeutic response end up stopping the medicine due to undesired effects.9

Biochemical availability of the pharmacologic agent may occur within hours after taking the first dose. It may, however, take weeks before the positive effect of an antidepressant is apparent. One theory as to why there is a delay of symptom relief is that complex changes must occur within neurotransmitter receptor sites in the brain before significant symptomatic change may be observed. The belief is that the presence of antidepressant medications promotes change in brain protein production at a cellular level leading to an increase in synaptic plasticity, perhaps even encouraging slow progress toward a physically healthier brain. What it means in the short term is that therapeutic support of the person in depression is essential, given the slow onset of medication effect.

Neurotransmitters chemically tend to be monoamines. Monoamine oxidase is an enzyme that breaks down neurochemicals such as serotonin, dopamine, and norepinephrine. Medication that inhibits the degradation of these neurotransmitters promotes higher levels of mood by increasing the quantity of available neuroactive chemicals.

MAOIs, as monoamine oxidase inhibitors are commonly referred to, were the first class of antidepressants to see clinical use, following their discovery in 1952. MAOIs are effective yet currently not a first-line drug due to a range of severe food-drug and drug-drug interactions that accompany them.

MAOIs have been found to be effective in a broad range of anxiety and mood disorders, especially depression. However, due to the risk of hypertensive crisis practitioners must be very selective for whom they prescribe MAOIs. The client must be able to understand potential risks and follow a very strict, low-tyramine diet.

MAOIs are very useful in the treatment of “atypical” depression (e.g. depression with hyperphagia, hypersomnia, leaden paralysis, or rejection sensitivity). Clinicians should also consider the MAOIs for use in clients exhibiting treatment resistant depression.¹⁰

Bupropion is an antidepressant distinctly different from the others. Chemically its structure resembles that of amphetamines and has the ability to increase available levels of the “brain reward” neurotransmitter dopamine. A spotty past has led to some hesitancy among prescribers. Bupropion was withdrawn from the market for a short time in the mid-1980’s subsequent to reports of a slightly higher incidence of seizures amongst bulimia clients. In 1989, bupropion returned to the market with a warning to avoid use in clients with a history of anorexia, bulimia, or seizure disorders.

Serotonin abnormalities are linked to many emotional and behavioral disorders including mood disorders, obsessive-compulsive disorder, and aggressive behaviors. The selective serotonin reuptake inhibitors (SSRIs) have the ability to effectively increase the amount of available serotonin within the brain. Increased levels of serotonin tend to occur quickly after initiation of medication therapy. Initial medication response may be seen in about two weeks; however full effect may not be observed for up to eight weeks from initiation of treatment.

Overall efficacy between the SSRIs in relieving depression appears similar. Choice of agent should be determined by matching medication characteristics with individual need. 

Serotonin dopamine activity modulators (SDAMs) are new drugs that tend to play the role of adjunct medication for major depression and schizophrenia treatment. Their somewhat dual nature lends some confusion as to whether they are antipsychotics that also treat depression or antidepressants that can be beneficial in the treatment of schizophrenia.¹¹  Whichever view wins out in the end, what is clear is that SDAMs work as a partial agonist of serotonin (5-HT1A) and dopamine D2 receptors. Placing them in the useful category for antidepressants, particularly in those for whom one antidepressant alone is just not enough.

Serotonin modulators (e.g. nefazodone, trazodone) are similar to SSRIs in effect though they operate by a slightly different mechanism. Special caution is indicated when liver damage is present due to the manner in which the body metabolizes these agents.

Combining the “high alert” system arousal effects of increased norepinephrine with the positive mood benefits of serotonin may be a good combination for some clients struggling with depression. The serotonin norepinephrine reuptake inhibitors (SNRIs) also tend to have a weak dopamine reuptake effect. Safety and tolerability of the SNRIs are similar to the SSRIs, although monitoring is warranted for an uncommon sustained rise in blood pressure.

Mirtazapine (Remeron) is an antidepressant without a home. It is neither a SSRI nor is it an SNRI. Its effects are similar, yet subtly different than either grouping, and because of those differences, it should be considered as an option in clients with treatment-resistant depression who are not responsive to SNRI or SSRI medications.¹³

Another odd medication is Milnacipran. This medication is a relatively new SNRI, but with a twist. It is currently approved by the FDA for use in the treatment of fibromyalgia, but not for use in depression.¹⁴

Cyclic antidepressants were discovered in the 1950’s. The first cyclic antidepressants were named “tri”-cyclic because their chemical structure somewhat resembled three interlocked rings when drawn out in scientific notation.⁸ Several other cyclic formulations have been discovered since the days of the three-ringers; however, tradition carries the name tricyclic forward for the general grouping despite its current descriptive inaccuracy.

Cyclic antidepressants find less common use than the current first-line SSRI and SNRI agents. The lack of use of cyclic antidepressants in part is due to a wider neurotransmitter effect, with more brain chemicals being shifted and a resultant broadening of potential side effect profiles.

The cyclic antidepressants have been associated with occasional cardiac problems. It is highly recommended that before prescribing any of the cyclic agents a baseline electrocardiogram (ECG) and cardiac history be conducted. In younger clients (less than 40) with a negative cardiac history, the ECG may not be warranted.¹⁵

Older, first-generation drugs remain a valuable resource. They are characterized by good efficacy, however, have a higher incidence of Parkinson’s disease-like neuromuscular symptoms (pseudoparkinsonism) and EPS (extrapyramidal side effects). EPS effects include such things as slow and diminished movements (bradykinesia), tremors, rigidity, subjective and objective restlessness (akathisia). Typical antipsychotics also carry a risk of developing a lasting choreoathetotic (spasmodic irregular) movement disorder known as tardive dyskinesia.

Further unwanted effects common to typical antipsychotics are the elevation of serum prolactin, a risk of a cardiac rhythm effect known as QT prolongation, feelings of sedation, and anticholinergic effects.¹⁶

Second-generation drugs are often the first choice in treatment for psychotic symptoms. They have a lower incidence of unwanted EPS as well as a reduced risk of tardive dyskinesia.¹⁷ What they lack, however, is a firm record of superior performance over the older typical antipsychotic agents which brings the realization that for any particular client, newer may not be superior to older. Treatment choices should be based on factors such as individual client response, side effect profile, and cost.

Atypical antipsychotics and clozapine have been associated with an increase in metabolic syndrome (e.g. hyperglycemia, dyslipidemia, and hypertension) as well as an increased risk of new onset diabetes. Weight gain is also a significant issue with atypical agents with clozapine and olanzapine having the greatest reports of increase. 

Clozapine is a stand-alone antipsychotic. It affects the dopamine D2 receptor sites, as do all of the antipsychotic medications. Clozapine is highly prized for its history of good effect on schizophrenic clients whose metabolism resist typical and atypical antipsychotic treatment.

The bad news, however, and the reason why clozapine is not a first-line antipsychotic, is not the adverse effects of weight gain and risk of metabolic syndrome. It is the presence of an unusually high risk of agranulocytosis. This abnormally low level of white blood cells in the body (agranulocytosis) occurs in approximately 0.38 percent of those being aggressively monitored, down from between 1 and 2 percent of clients who in the past were less carefully followed.¹⁸ Some of this tremendous improvement may be due to the FDA requiring practitioners’ prescribing clozapine to weekly monitor white blood cell counts (WBC) for the first six months, then biweekly for the next six months. After that, WBC checks can be every four months for the duration of treatment making clozapine a high maintenance medication for client and prescriber.

Mood stabilizers are medications that buffer the dramatic emotional rollercoaster ride which accompanies bipolar affective disorder as well as other conditions possessing a strong mood component such as schizoaffective, manic, or major depressive syndromes.¹⁹ The term mood stabilizer applies to medications that alleviate the intensity or the frequency of depressive, hypomanic, manic or mixed episode swings in clients with bipolar affective disorder (aka manic-depression). Mood stabilizers are the mainstay treatment for acute mania. They are used to induce remission in those individuals experiencing symptoms of hypomania, manic episodes, and aid to stabilize mood swing cycles into a maintenance range closer to what that person’s normal would be.

Lithium and a select group of antiepileptic medications form the mood stabilizer psychopharmacology group. Studies of these agents show similar response rates, of between 50 to 60 percent, in clients with acute mania. Choice of agent, therefore, revolves around previous experience for the client, comorbid medical conditions that are present, and side effect profiles of the drug.

Lithium, in particular, a purified mineral straight from a chemist's table of core elements, has a tricky set of potential unwanted effects, starting with the renal system. Clients with compromised renal function may not be able to excrete lithium efficiently and therefore are at risk for lithium intoxication. Common side effects of lithium therapy include polyuria, loose stools, tremor, cognitive effects such as confusion, and weight gain. Around 10 to 20 percent of clients on lithium therapy develop hypothyroidism. Tremors are so common with lithium use that up to 65 percent of clients will experience them to an extent. Sudden worsening of an existing tremor or sudden appearance of a tremor that had not previously been present can be a sign of impending lithium toxicity.²⁰ Interestingly, recent work with lithium suggests it possesses positive unanticipated effects such as neuroprotection and a significant reduction in suicidal acts for those using it.²¹

The alternative mood stabilizers are closely related to the antiepileptic medication family, and also require careful monitoring. Carbamazepine, for example, may cause dose-related diplopia (double vision) or ataxia (the inability to coordinate muscle movements). Lamotrigine may cause nausea, skin rash, dizziness, or headache. Valproic acid can cause liver problems, gastrointestinal distress, weight gain, and even alopecia (hair loss). Oxcarbazepine is associated with sodium loss and can cause hyponatremia as well as somnolence, dizziness, nausea, or dizziness.

It is unclear how mood stabilizers work. Current thought is that they are able to alter the ion channels of cell walls in the central nervous system. Many also increase available GABA levels.

Psychostimulants affect the dopaminergic and noradrenergic neurotransmitter systems, causing the release of catecholamine’s from storage sites at synapses in the central nervous system (CNS). Psychostimulants reduce feelings of fatigue, promote alertness and wakefulness, increase the ability to concentrate, and have possible mood enhancing properties. In current psychiatric practice, their use is largely limited to attention deficit and sleep disturbance disorders such as narcolepsy.

Historically attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD) were believed to be a time-limited condition of childhood that must be diagnosed before the age of twelve to exist.²⁴ Data shows that between 8 to 11 percent of school-age children are affected sufficiently to warrant a diagnosis, and between 40 and 60 percent of these go on to adulthood with significant adult ADHD symptoms.^25,26

Treatment for ADHD is beginning to shift from strict pharmacotherapy alone toward changes in the environment and stimulation of individuals both without, or still most common, with medication. Behavioral parent training, behavioral classroom management, and behavioral psychotherapy utilize psychostimulants to suppress symptoms while non-pharmaceutical treatment is employed to handle root issues. It is important therefore to remain aware that psychostimulants continue to be present, and indeed the mainstay first-line treatment for attention deficit conditions both in youth and adults, despite efforts to go non-pharmaceutical.²⁷

Available studies fail to show improvement in school performance in children to whom psychostimulants have been prescribed. However, the use of stimulant medication has, in studies, demonstrated improvement in behavior in all children to whom they are given (e.g. children with ADHD, learning disabilities, depression, and even normal children), not just those with ADHD. Adults report an increase in ability to concentrate while taking prescription psychostimulants.

Atomoxetine (Strattera) is a non-stimulant approved for use in children older than six years of age, adolescents, and adults diagnosed with ADHD. It is not a true psychostimulant. Instead, it is more closely related to the SNRI medications. Despite a different mode of action, it has stimulatory effects on the sympathetic nervous system and been well received as a psychotherapy alternative, especially in instances where there exists a potential for abuse in the individual receiving treatment.