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Table 9: Drug interaction of antidepressants with tamoxifen (Nolvadex)

Pharmacodynamic interactions

The cytochrome P450 enzymes also influence the effects of antipsychotic drugs on the body i.e. its pharmacodynamic effects. The coadministration of psychotropic drugs can result in the potentiation or addition of the effect of another.

The risk of agranulocytosis, the very serious blood dyscrasia side effect associated with Clozapine (Clozaril) monotherapy is amplified when combined with carbamazepine (Tegretol), imipramine (Tofranil) and mirtazapine (Remeron) which have also been reported to exhibit the same side effect. The additive effects can be devastating on the immune system of patients.

Even common food and vegetables like broccoli, brussells sprout, and charred grill meat affect the CYP isozymes activity. Grapefruit juice is a well known inhibitor of the CYP3A4/5/7 isozymes and interacts with their substrates.

The smoke inhaled from the environment and tobaccos are also known to affect CYP isozymes.

Selective serotonin reuptake inhibitors (SSRIs), when given with B-blockers, may cause additive depressant effects on the heart that manifests as bradycardia. In this case, SSRIs increased the concentration of the beta blocker by inhibiting the CYP isozymes responsible for its metabolism.

TCAs, when given with type 1A anti-arrhythmic drugs, cause conduction abnormalities in the heart that may lead to arrhythmias. Also, when combined with sublingual nitrates, they may not be orally absorbed well due to their anticholinergic effects manifesting as reduced oral secretions and dry mouth.

When antipsychotics are combined with alcohol, TCAs, benzodiazepines and antihistamine, the result is additive sedation. Furthermore, risperidone (Risperdal), chlorpromazine (Thorazine), clozapine (Clozaril) and pimozide (Orap) when combined with antihypertensives and TCAs have greater potential of causing orthostatic hypotension.

Tricyclic antidepressants potentiate the stimulation exerted by amphetamines that may lead to cardiac effects being enhanced.

Serotonin syndrome is another potentially lethal drug interaction that occurs with use of many psychotropic drugs. It has been discussed in detail in the previous sections. Patients taking MAOIs need up to wait 2 weeks before other antidepressants or any other drugs are safe to administer.

Norepinephrine reuptake inhibitors should be cautiously administered with beta-2 agonists like albuterol (Proventil) as the cardiovascular affects of the latter are potentiated and an increase in heart rate and blood pressure may be experienced. Also, coadministration of SNRIs and SSRIs cause alterations of the activity of anticoagulants which can result in increased bleeding times. Therefore, patients on warfarin (Coumadin) should be closely monitored when given these medications.


Side effects

Side effects are expected adverse drug events related to the pharmacological effects of the medication. They are often the “menace” that accompanies the therapeutic benefits. However, some side effects are used to the patient’s advantage. For example, the mild antidepressant, trazodone (Oleptro), may be prescribed in patients who require its sedative effects to help them sleep at night.

The following side effects are common in many psychotropic drugs and are discussed briefly followed by its in-depth discussion as it relates to each group of psychotropic drugs.

Orthostatic hypotension

A sudden drop in blood pressure (> 20 mmHg for systolic or 10 mmHg for diastolic) when a patient stands up and accompanied by a dizzy spell has occurred in patients on a combination of antidepressants. Some SSRIs and TCAs, and almost all MAOIs (except moclobemide) cause significant hypotension. Isolated cases have been published reporting alarmingly low blood pressures when SSRI’s were given in combination with small doses of TCAs in 2 elderly patients [73]. Similarly, a study in Germany concluded that a strong correlation was found between the decrease in blood pressure levels and serum drug concentrations of SSRIs and TCAs. Not only this, but the newer generation antipsychotics are also believed to have significant orthostatic effects even though they are appear to have more benign side effect profiles. Antipsychotics that cause orthostatic hypotension are clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), aripiprazole (Abilify), and quetiapine (Seroquel) [74].


Sexual dysfunction and hyperprolactinemia

Sexual dysfunction is a common side effect of most psychotropic medications, particularly antipsychotics. In some cases libido, sexual drive and function seem to improve after discontinuation of these drugs. The dysfunction occurs as a result of the dopamine antagonism at its receptor and transporter sites, and also partly due to increased prolactin levels which is mediated by dopamine.

Typical antipsychotics cause sexual dysfunction more than the newer atypical agents. Olanzapine (Zyprexa), quetiapine (Seroquel) and clozapine (Clozaril) show none to moderate prolactin elevation when compared to risperidone.

Long-term benzodiazepine use is also associated with sexual dysfunction. Lithium, when given alone to treat bipolar disorder, seem to have less effect on sexual functioning when compared to its co-administration with a benzodiazepines [75].

Medications like phenothiazines, butyrophenones, metoclopramide (Reglan), and risperidone (Risperdal) block the action of dopamine on the pituitary gland [76]. A rise in prolactin levels is associated with a host of sexual problems such as galactorrhoea, gynecomastia, amenorrhea, infertility, loss of libido, and erectile dysfunction.

Selective serotonin reuptake inhibitors were once wrongly believed to cause excessive elevation of serum prolactin levels. No long term large scale studies proved its hypothesis. On the contrary, SSRIs actually cause very little increase in prolactin levels. Out of all the available SSRIs, only patients treated with paroxetine (Paxil) were seen with clinically significant elevated prolactin levels. Fluoxetine (Prozac) also elevates prolactin levels but only with post-menopausal women (77).


Liver/kidney dysfunction

Clozapine (Clozaril) also causes liver damage in some patients. The damage is similar to the cholestasis that occurs in with phenothiazine use. Only a benign rise in ALT was seen in these patients, however, serious liver damage have also been reported in other cases.

Similarly, TCAs and MAOIs are believed to have the highest hepatotoxic potential amongst antidepressants especially in comparison to the newer drugs like selective serotonin reuptake inhibitors [78]. Amineptine, although not prescribed in the US, causes cholestatic liver disease and some reports have shown it to also cause necrosis. Imipramine (Tofranil) also has the potential to cause cholestatic jaundice.

Amphetamines have been reported to cause acute liver damage, particularly with intravenous use and over the safe and recommended doses, though the elevation of serum AST and ALT levels has not been clearly established. The exact mechanism of liver injury is unknown, however, since amphetamines undergo extensive metabolism in the liver, the formation of a hepatotoxic metabolite is a strong possibility.

The typical clinical picture of amphetamine-induced hepatitis is fatigue, weakness and jaundice, which may be clinically apparent 3-14 days after ingestion of the drug. AST, ALT and LDH values may show a marked increase. Acute liver failure in such cases may also be accompanied by other organ damage.

Renal toxicity is not frequently observed with psychotropic medication but since many of these drugs are eliminated by the kidneys, it is important to recognize the effects of pre-existing kidney disease on renal excretion so that dose adjustments may be made accordingly.


Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the abnormal release of antidiuretic hormone (ADH) from the posterior pituitary gland that results in decreased diuresis and consequently, fluid overload in the body. The syndrome manifests as a slowly progressive hyponatremia with chronic pain. The patient history may hint at drug use, CNS injury and tumors.

SIADH is associated with hyponatremia without edema. A severe form of hyponatremia and unresolved volume status can result in patients experiencing lethargy, delirium, headache, confusion, nervousness, apathy, irritability, and in very severe cases, convulsions, and coma. Even deaths have resulted from untreated SIADH. Many of the psychotropic drugs that cause SIADH have the propensity to affect the elderly patients, especially those above 65 years of age. Although tricyclic antidepressants are associated with SIADH, they have not been consistently observed.

Selective serotonin reuptake inhibitors, haloperidol (Haldol), phenothiazines, monoamine oxidase inhibitors and barbiturates are all associated with SIADH. Sometimes the symptoms of depression may be hard to distinguish from that of SIADH, making the diagnosis a difficult one. Laboratory values are needed to correlate clinical symptoms and affirm or rule out the diagnosis.



Bone Mineral Density (BMD)

Many psychotropic drugs also cause a decrease in bone mineral density. The side effect is attributed to the dopamine inhibition that leads to hyperprolactinemia that may in turn lead to secondary hypogonadism. Prolactin interferes with the pulsatile release of Gonadotropin-releasing hormone (GnRH) and inhibits follicle stimulating hormone (FSH) and luteinizing hormone (LH) production. Schizophrenic patients who are on long term antipsychotic medications are especially susceptible to this particular side effect. In general, vitamin deficiencies can occur with many psychotropic drugs, such as B6, calcium, and magnesium deficiencies, among others.

A study conducted by the Massachusetts General Hospital in Boston reported that significant morbidity is associated with low bone density prompting clinicians to consider its diagnosis as an integral part of patient management on long-term antipsychotic medications [79].

On the other hand, tricyclic antidepressants are known to possess protective effects against osteoporosis and can be used when severe bone mineral density loss is suspected [80].

The “menacing” side effects mentioned above of antipsychotics, antidepressants, benzodiazepines and other anxiolytics, sedative-hypnotics, stimulants and mood stabilizers are discussed in more detail in the succeeding pages.

Antipsychotics

As mentioned in the last section, antipsychotics have a broad side effect profile. They cause extrapyramidal symptoms, weight gain, thyroid dysfunction, and metabolic disturbances, hyperprolactinemia, agranulocytosis and sexual dysfunction.

Extrapyramidal symptoms (EPS)

Extrapyramidal symptoms are drug-induced side effects, a consequence of dopamine blockade. All medications that block dopamine or interfere with its function, synthesis, release and reuptake will exhibit extrapyramidal symptoms as side effects. Antipsychotics interfere with normal functioning of dopamine.

Extrapyramidal symptoms include dystonia, akathisia, tremors and rigidity (parkinsonian symptoms) tachycardia, hypotension, nightmares, sexual disturbances, and seizures. Their appearance and severity vary individually and overlap, making it the more difficult to diagnose them. Patients with severe EPS may need treatment options. Dose titration or a switch to another antipsychotic (with lesser EPS risk) may be needed if the patient cannot tolerate the EPS. Discontinuation should be done gradually to prevent relapse and withdrawal symptoms. Medications that help manage EPS are anticholinergic medications such as benztropine (Cogentin) and diphenhydramine (Bendaryl). Beta blockers (e.g. propranolol) and benzodiazepines (e.g. lorazepam) are also used to control restless motor movements. EPS screening measures should be used in patients taking antipsychotics. The 12-item Abnormal Involuntary Movement Scale (AIMS) is commonly used to assess motor movements and the severity of symptoms.

Long-term use of typical antipsychotics increases the likelihood of tardive dyskinesia, which is described as involuntary, purposeless, repetitive movements occurring in various parts of the body. The newer drugs, atypical antipsychotics (e.g. clozapine) are less likely to cause tardive dyskinesia [81].

Another very common side effect of antipsychotics is the effect on overall thyroid function associated with their use [82]. In 2007, researchers in Johns Hopkins suggest that the weight gain is caused by an increase of the enzyme adenosine monophosphate-activated protein kinase (AMPK) in the brain that is normally triggered by the biochemical histamine. What’s interesting is that the study showed that histamine and clozapine act on the same histamine receptor to elevate AMPK levels, making the connection between appetite stimulation and antipsychotics (83).

A study by Khalil et al. found that patients who took phenothiazines and TCAs should be closely monitored for the development of thyroid function abnormalities. Phenothiazines and atypical antipsychotics change iodine uptake and decrease thyroid - stimulating hormone's (TSH's) sensitivity to thyroid-releasing hormone (TRH) stimulation. Only patients at risk for developing thyroid dysfunctions need to be monitored when they receive typical and/or atypical antipsychotic drugs. Currently, there are no specific recommendations proposed for the thyroid function monitoring in patients receiving any other psychopharmacologic drug (207).

Antipsychotics are also known to elevate blood glucose in diabetic geriatric patients. A study published in 2009, Archives of Internal Medicine, one of the JAMA/Archives journals, reported acute elevation of blood glucose levels after the start of therapy. Moreover, a document released by the American Diabetes Association, warn that mentally ill patients who are not diabetic at the start of antipsychotic therapy may be at an increased risk of developing an impaired glucose intolerance or pre-diabetes (84).

Clozapine, as discussed in the previous section, causes a severe decrease in white blood cells (neutropenia) during the first few months of therapy. Unresolved neutropenia (PMP <500 cells/μl) results in agranulocytosis, a marked near-absence of circulating white blood cells (85). The side effect was widely known prior to its FDA approval. However, because of its demonstrated efficacy in treatment-resistant schizophrenia and less liability to cause EPS, it was approved with strict orders to maintain bi-weekly hematologic monitoring for the entire duration of therapy. Moreover, at the first signs of neutropenia, patients should be monitored very closely for the onset of fever and other signs of infections.

As mentioned previously, prolactin levels may rise in patients taking atypical antipsychotics (e.g. risperidone). This is due to the drug’s blockade of the dopamine in the brain. Aside from mood regulation, dopamine also inhibits the release of prolactin from the pituitary glands. The manifestations of hyperprolactinemia are seen in the breast enlargement and secretion of milk of patients, regardless of gender. Risperidone has a high affinity for D2 receptors. It produces a rapid, dose dependent rise in the prolactin levels that is quite similar to that of haloperidol; however, it must be noted that studies did not prove this rise to be directly related to the clinically related adverse effects associated with elevated prolactin levels at usual doses. A study showed that 90% of patients taking the drug had an increase in serum prolactin levels whereas only half of the patients taking olanzapine had experienced the same [86].

Clozapine has a lesser affinity for the dopamine receptors and cause lesser degree dopamine inhibition. Quetiapine has shown comparable prolactin level effects to placebo in some studies.

A study that compared haloperidol with placebo found that the drug significantly raised serum prolactin levels, up to a 9-fold increase after only a single injection. The weeks after the start of treatment showed an expected persistent rise of prolactin levels.

Phenothiazines also cause elevated serum prolactin levels that range between two to tenfold when compared to baseline. An initial steep rise is seen in the first three days of treatment followed by a lesser but sustained rise in the following weeks.

Heterocyclic antidepressants have also been thought to cause mild elevation of serum prolactin levels, however, further studies are needed to validate the hypothesis. A study showed that patients treated with the two tricyclic antidepressants, clomipramine and amitriptyline, showed a temporary rise in prolactin levels at the start of therapy. After sustained administration of the drugs for 28 days, confusing results were seen; the patients treated with clomipramine and amitriptyline showed a significant increase and decrease in prolactin levels, respectively [87].

Another side effect of antipsychotics is sexual dysfunction such as impotence, decreased sexual interest and ejaculation problems. However, these side effects disappear as soon as the drug is discontinued.

Pooled FDA studies point to the most fatal adverse effects of older and new antipsychotics – sudden death in geriatric patients with dementia-related psychosis. The black box warnings on the labels of the drugs listed above are actually about this life-threatening risk. Although the exact causes of the deaths were not identified, a series of possible effects may play a role such disturbances in cardiovascular conductance, EPS, and anticholinergic effects (88).

Antidepressants

Antidepressants exert their pharmacological actions differently to treat depressive symptoms. Likewise, the side effects also vary according to the neurotransmitter or receptor system being targeted by the drug, and may overlap as well. Generally speaking, their side effects improve with time. The most common of these are:


  • Erectile dysfunction

  • Dry mouth

  • Drowsiness

  • Restlessness

  • Weight gain

  • Constipation

  • Nausea

  • Headaches

Tricyclic antidepressants (TCAs)

The unpredictable and much more pronounced side effects of TCAs have made it unpopular with prescribers and patients alike in the last decade. TCAs cause blurred vision, drowsiness, dysuria, sweating, and constipation. Some of these side effects may decrease after 7-10 days of therapy.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors also cause serious adverse effects. They are usually avoided as first line treatment for this very same reason and relegated to being a secondary treatment option when:



  • The patient did not respond to the first line antidepressants (usually SSRIs)

  • The patient has low tolerance for the side effects of the other class of antidepressants

  • The patient is experiencing weight gain and unusual sleeping patterns

Nausea, shaking and trembling, insomnia, and blurred vision are commonly associated with MAOI use.

These drugs also have the potential to cause sudden elevation of blood pressure (hypertensive reactions) with patients experiencing severe headache, stiff neck, chest pain and/or palpitations. The emergence of such symptoms should prompt a medical emergency.

Monoamine oxidase inhibitors cause orthostatic hypotension in most patients being treated with traditional monoamine oxidase inhibitors. The MAOI-A, selegiline, is particularly intentionally co-administered with levodopa to augment the latter’s dopaminergic effects on the Parkinsonian brain. The concomitant use, however, also produces orthostatic hypotension. Phenelzine, a MAOI-B inhibitor, also causes significant hypotension. Generally, the cardiovascular symptoms appear after 2-3 weeks after the initiation of therapy, and their severity is directly proportional to the peak plasma levels of the drugs. It is postulated that changes in dosing intervals might still not be enough to have a significant impact on avoiding orthostatic hypotension and interventions that increase intravascular volume might just prove to be more helpful.

MAOIs come with severe dietary restrictions. When combined with tyramine-containing foods such as wine, chocolate and cheese, they cause a hypertensive crisis, a medical emergency (195).

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs especially fluoxetine have many reported side effects on all body systems. On the cardiovascular system, it causes palpitations and rarely, arrhythmias and hypotension. On the nervous system, it causes emotional liability, akathisia, and other movement dysfunctions relating to balance. Bruxism and depersonalization issues along with euphoria have also been reported, although rarely, with the use of fluoxetine (Prozac). Additionally, there have been rare reports of patients suffering from hypertonia, an increase in libido and myoclonus. Paranoid reactions and gynecological disturbances have also been reported with fluoxetine use.

SSRIs have a black box warning cautioning patients and clinicians about the increased risk of suicidal thoughts in children and adults with this class of antidepressants. The risk was first reported in 1990, shortly after the drugs were introduced.

Antidepressants acting on the serotonin system can precipitate serotonin syndrome. Serotonin syndrome is a potentially life-threatening toxic state brought on by excess serotonin within the CNS. Excessive serotonin activity can lead to cognitive, autonomic and somatic disturbances. The usual clinical picture comprises of increased sweating, palpitations, dilated pupils, myoclonus, and hyperreflexia. The body temperature can rise up to 106 (degree Fahrenheit). Metabolic acidosis, seizures and even renal failure can occur if no immediate treatment is given. These drugs are therefore best avoided in patients diagnosed with serotonin secreting tumors (neuroendocrine tumors).

Serotonin syndrome usually occurs after a dose increase or overdose of a serotonergic agent or the addition of a second agent. The psychotropic agents implicated in serotonin syndrome are:


  • SSRIs

  • TCAs

  • MAOI-A

  • Buspirone

  • Amphetamines

  • Lithium

  • St. John’s Wort

  • LSD

Long-term use of SSRIs and TCAs is also linked to type 2 diabetes [89]. Patients taking these medications for a prolonged period of time are believed to be more at risk of developing diabetes than others. Worsening of diabetes and loss of glycemic control can also occur while on these medications.

Selective serotonin reuptake inhibitors have a dose dependent effect on sexual dysfunction. Drugs like fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil) and sertraline (Zoloft) show significant effects on the sexual functioning of the users. Significant differences were observed with each drug individually; paroxetine causes delayed ejaculation and orgasm, and impotence compared to the rest of the medications mentioned [90]. Priapism, on the other hand, has been reported with use of all selective serotonin reuptake inhibitors. Fluoxetine is so far only associated with decreased libido, however, some women have reported experiencing orgasmic dysfunction such as anorgasmia.

Norepinephrine reuptake inhibitors (NERIs)

Similarly, norepinephrine reuptake inhibitors like atomoxetine also have profound effects on almost all parts of the human body. It affects the gastrointestinal system and may cause dry mouth, nausea, constipation, and heartburn. Fatigue, chills and jittery feelings may also be experienced in response to atomoxetine use. Effects on the CNS include excessive somnolence, tremors, headaches, paresthesias and also dizzy spells.

Atomoxetine, like other antidepressants acting on the serotonin system, may cause erectile dysfunction and decreased in libido [91]. Ejaculation disorders and menstrual irregularities have also been reported with NERIs.

Benzodiazepines

Patients on benzodiazepines commonly experience dizziness, drowsiness, orthostatic hypotension, difficulty concentrating and diminished level of alertness.

Benzodiazepines cause orthostatic hypotension by decreasing left ventricular contractility and reducing cardiac output. Temazepam is one of the most significant drugs to cause orthostatic hypotension when compared to placebo.

Benzodiazepines also have muscle relaxant properties that can result in impaired coordination. Studies show that elderly patients are more prone to experience falls after the use of these drugs. The combined effects of diminished alertness and impaired muscle coordination are known to cause road traffic accidents when driving under their influence. Sexual dysfunction is also a fairly common side effect of benzodiazepines.

Paradoxical adverse reactions are also known to occur with benzodiazepine use in patients on high dose regimens, populations who have been taking the drug for prolonged periods of time, children, and recreational users. Patients may experience more frequent seizure activity, violence and aggression. Some reports have seen an increased risk of suicidal tendencies. Some patients on long-term therapy may also experience cognitive impairment.

Diazepam (Valium) is associated with drowsiness, fatigue, muscle weakness, ataxia, depression, dysarthria, slurred speech, headaches, tremor, diplopia, and hypotension. Acute hyper-excited states, anxiety, irritability, rage, psychoses, sleep disturbances and inappropriate responses have also been seen with its use.

Anxiolytics

Buspirone (Buspar) is used to treat symptoms of anxiety, such as fear, tension, irritability and dizziness. It can cause fast and irregular heartbeat, nausea, dizziness, impaired coordination, depressed moods, restlessness, diarrhea, and insomnia.

Propranolol (Inderal) is a beta-blocker often prescribed to treat anxiety. Its side effects include hypoglycemia, hypotension, decreased heart rate and increased airway resistance (contraindicated in asthmatics).

Gabapentin (Neurontin) is another off label anxiolytic that is prescribed fairly commonly. It causes fever, chills, tremors, increased susceptibility to bruises and body aches, and swelling of extremities.

Sedative-hypnotics

One of the main problems associated with sedative use are their addictive properties and abuse potential. Just like benzodiazepines and other anxiolytics.

Commonly associated side effects with sedative-hypnotics are the marked increase in depression, suicidal tendencies and thoughts. Anxiety, aggression and restlessness are seen to improve but at the same time may be paradoxically caused. With prolonged use and at inappropriately high doses, hallucinations may occur with sedative usage.

When taken over a prolonged period of time, sedatives are known to cause physiological and psychological dependence. Withdrawal symptoms are experienced when patients take themselves off these medications suddenly. Symptoms of drug withdrawal range from restlessness and insomnia to severe reactions such as convulsions, and in rare instances, even death. Similarly, fatal events can occur if sedatives are combined with other central nervous system depressants like alcohol.

Patients on barbiturates who suddenly cease therapy exhibit strong withdrawal and rebound symptoms, and rapid eye movement (REM) sleep. Doses need to be calculated accurately because fatalities are known to occur even with a relatively small overdose.

Mood stabilizers

Lithium requires close monitoring to avoid toxicity. Its toxicity is due to the fact that with certain populations, its therapeutic dose overlaps with its toxicity dose, leaving a very narrow window of safety. Signs and symptoms of lithium toxicity are enumerated on the table below.


Early stages

Late stages

Hyperactive DTR

Nausea

ECG abnormalities

Fever

Tinnitus

Anorexia

Decreased urine output

Unconsciousness

Vertigo

Vomiting

Decreased blood pressure




Drowsiness

Diarrhea

Irregular pulse




Weakness

Twitching

Coma




Ataxia

Lethargy

Seizures





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