Side Effects of Psychopharmacotherapy Research Paper

Most psychoactive drugs exert their effects first by interfering with the communication between nerve cells (neurons). At the molecular level this occurs by their interaction with receptors of neurotransmitters located on the surface or inside the neuron. This step initiates a cascade of events that eventually lead to alterations in the neurotransmitter and/or hormonal systems. Nonspecific drug action at any level in this process results in side effects.

The term side effect implies an undesirable (adverse) drug effect; a particular side effect of a drug for a given condition may be a desirable one for another condition. For instance, benzodiazepines may be prescribed for anxiety disorders, but as a side effect they cause sedation. On the other hand, they may also be prescribed for the treatment of insomnia as a primary indication. Indeed, the psychoactive potential of several drugs was discovered as a result of unexpected but beneficial side effects on psychiatric patients who were taking these drugs for other therapies (see below). The spectrum of drug effects originate largely from their effects on multiple neurotransmitter systems, and the interactions of these systems with each other and other sites of action in the central nervous system.

At times it is a challenge in the practice of psychiatry to be able to determine if a given behavior is a symptom of an illness or a side effect of drug treatment, as the latter may mimic the former. For instance, untreated patients with schizophrenia frequently display decreased spontaneity, lack of motivation, and social isolation. These symptoms resemble some of the extrapyramidal system side effects induced by conventional antipsychotics. A practical management of this potential difficulty involves careful assessments of the patient’s functions e.g., sleep patterns, daily living routines, and sexual function prior to treatment.

1. Historical Perspective

Treatment with substances that alter mood, thinking, and cognition date back to prehistoric times (Spiegel 1996). Various psychoactive substances have been used in religious ceremonies, rituals, and for healing of pain.

Alcohol is the oldest drug used for its calming and sedative effects. The disinhibition caused by alcohol is described in the first book of the Old Testament. Apart from consumption in social settings, alcohol was introduced for medical use in the nineteenth century as a general anesthetic. The narrow therapeutic index (the ratio of toxic over desired dose) of alcohol limited its usefulness for this purpose.

Opium (papaver somniferum), hellebore, and rauwolfia roots are among the oldest compounds that were extracted from plants in prehistoric and ancient times. Morphine was isolated from opium in the beginning of the nineteenth century and has been available as an analgesic with considerable addiction potential.

In ancient times, different forms of hellebore root were used as emetics, laxatives, and for mental conditions such as mania and melancholy. Risk of seizures limited its use.

Rauvolfia serpentina roots were used by Indians to treat snake bites and also in some mental conditions. Reserpine, a rauvolfia alkaloid was noted to have a calming effect in patients with schizophrenia. Because reserpine induces severe depression as a side effect, its use as an antipsychotic has been abandoned.

Cocaine is an alkaloid derived from the shrub Erythroxylon coca; it originated in South America where it was used for its stimulating effects. It was isolated in the nineteenth century and is still used as a local anesthetic. Paranoid delusions, hallucinations, seizures, and dependency are some of the adverse effects of cocaine.

The discovery of psychoactive medications has resulted from the side effect profiles of drugs used in medicine. For instance, the antipsychotic chlorpromazine was initially used to help patients with presurgical preparation and as an adjuvant to anesthetics. Its sedative and calming effects easily found its way to treatment in psychiatric disorders as a primary indication soon after its antipsychotic properties were discovered. Similarly, iproniazid (an antidepressant of the monoamine oxidase inhibitor (MAOI) type) was originally developed as a drug for the treatment of tuberculosis. In clinical drug trials, patients treated with this drug were observed to become stimulated and cheerful. This observation lead to the investigation of the antidepressant effect of iproniazid.

2. Genetic Factors And Side Effect Vulnerability

Side effects are not uniformly observed in everyone. While some patients never develop a certain side effect, others are affected from day one of treatment. The strongest determinant of this interindividual variation is believed to be in the genetic complexion. Variations in the sequence of the DNA called polymorphisms are believed to play a role in expression of a wide spectrum of reactions to drugs: from full response to nonresponse; minimal to severe side effects. The completion of the Human Genome Project will aid in the identification of patient subgroups according to their drug response patterns. For instance, certain variations in the gene that codes for the enzyme CYP2D6 lead to slow metabolism of some drugs such as tricyclic antidepressants, therefore these patients run higher levels of drugs and are more vulnerable to side effects (Schatzberg and Nemeroff 1998). The application of pharmacogenetics will be the identification of drugs that will be both efficacious and well tolerated for each individual according to his or her genetic makeup.

3. Assessment And Management Of Side Effects

Compared to the rating scales used to assess the symptoms of diseases, there are relatively few rating scales for the assessment of side effects. The most comprehensive of these is the Systematic Assessment for Treatment Emergent Events which has been designed for use in clinical drug trials. Udvalg for Kliniske Undersogelser Side Effect Rating Scale is also comprehensive and was developed for use in clinical trials and in routine practice. The Rating Scale for Extrapyramidal Side Effects (Simpson–Angus Extrapyramidal System Scale), Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale were developed to measure the extrapyramidal system side effects, akathisia, and dyskinetic movements, respectively, that are associated with antipsychotic drug use (American Psychiatric Association 2000). Even though each side effect ultimately requires individual management, a comprehensive approach is vital for general management. Such an approach involves a baseline assessment, careful choice of medication, patient and family education, minimization of the number of drugs (to decrease potential side effects and to avoid drug interactions), single bedtime dosing, the availability of clinicians to discuss the side effects, adjustment in dosage, counteractive drug treatment, and continuous assessment.

4. Noncompliance

Among factors that play a role in treatment noncompliance, such as denial of the illness and lack of supervision, one of the strongest predictors is early onset and persistence of side effects. Noncompliance by itself is a predictor of relapse in patients with chronic mental disorders who are recommended to receive lifelong maintenance treatment. One of the studies in this area found that half of the schizophrenic patients took less medication than recommended, and the reluctance was associated with the side effects of antipsychotic drugs (Van Putten 1974). On the positive side, many studies indicate improvement in treatment compliance with patient education. Particular approaches in patient education have been proposed that maximize the information conveyed while avoiding suggestibility (Balon 1999).

5. Classification Of Side Effects

One of the common characteristics of psychoactive drugs is their capability to cross the blood-brain barrier and reach the central nervous system. Consequently, side effects of psychoactive drugs may be generated both centrally and peripherally. Here, the distinction between drug action and drug effect is also relevant: drug action refers to alterations produced by the drug at the molecular level, whereas drug effect (as well as side effect) refers to the observed reactions of the organism. Below, we will examine the behavioral side effects of psychoactive medications; a review of physiological systems is beyond the scope of this chapter and can be found elsewhere (Schatzberg and Nemeroff 1998).

5.1 Autonomic

The autonomic nervous system controls homeostasis in the different functional systems in the body mostly through involuntarily mechanisms. Major neurotransmitter systems involve those of acetylcholine and norepinephrine ( β or α receptors).

Autonomic side effects of psychoactive drugs are most commonly due to anticholinergic effects. Because acetylcholine is widely distributed in the central and peripheral nervous systems, adverse anticholinergic effects can be observed both behaviorally and systemically.

Most antiparkinsonian (benztropine, trihexiphenidyl) and the majority of the antidepressant and antipsychotic drugs produce anticholinergic effects. Among the tricyclic antidepressants, tertiary amine tricyclics (amitriptyline, clomipramine, doxepin, imipramine, trimipramine) produce more anticholinergic side effects compared to secondary amine tricyclics (desipramine, nortriptyline, protriptyline) and tetracyclic antidepressants (amoxapine, maprotiline). Compared to tricyclic antidepressants, anticholinergic side effects with selective serotonin reuptake inhibitors (SSRIs) are minimal. Conventional low-potency antipsychotics (drugs in this category, such as chlorpromazine, thioridazine, and mezoridazine require higher doses to produce equal efficacy than the high-potency antipsychotics) have significant anticholinergic properties compared to high-potency antipsychotics (fluphenazine, haloperidol, perphenazine, pimozide, thiotixene, trifluoperazine). Among the new generation antipsychotics, clozapine has the most potent anticholinergic effects, as well as having properties of acetylcholine release. Olanzapine also possesses anticholinergic effects, but less than clozapine. Risperidone, queitapine, and ziprasidone have minimal anticholinergic activity. Peripheral anticholinergic effects include warm skin, flushing, dryness, dilated pupils (and blurred vision), increased intraocular pressure, dry mouth (if unrecognized this can cause dental problems, such as caries), tachycardia (increased heart rate), reduced acid secretion in the stom-ach, reduced pulmonary secretions, diminished bowel motility (constipation), urinary retention, and delayed or retrograde ejaculation.

Central anticholinergic effects of psychoactive drugs involve features such as memory impairment, confusion, disorientation, delirium, visual hallucinations, and worsening of preexisting psychotic symptoms. Combination of psychoactive drugs with anticholinergic effects, such as a tricyclic antidepressant, and a low-potency antipsychotic will highly increase the likelihood of an adverse reaction. Geriatric patients are particularly sensitive to anticholinergic side effects and deserve special consideration in the choice of psychoactive drugs and evaluation of a deteriorating course of their clinical situation.

5.2 Dependence

Dependence is an important component of the side effect spectrum of some of the psychoactive drugs (barbiturates, benzodiazepines). The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition defines substance dependence as a maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three or more of the following criteria: tolerance, withdrawal, consumption of large amounts or over a longer than intended time period, persistent desire to cut down, significant effort to obtain the substance, social, occupational sacrifice, and continued usage despite known hazards. It is of note that in this definition a biopsychosocial approach is undertaken. The treatment models for dependency are conducted in a multidisciplinary fashion that address physical, psychological, and environmental factors. Chronic drug use involves tolerance, physical dependence, and psychological dependence. Even though related, tolerance and physical dependence are different concepts:

Tolerance refers to the need of increased amount of a drug with repeated usage in order to achieve the same magnitude of effect. Interestingly, not all of the behavioral effects of drugs show similar tolerance patterns; in the case of benzodiazepines, for instance, tolerance develops for the sedative effects, but not for the antianxiety effects. Tolerance is a reversible condition; abstinence from the drug over a period of time will reduce the amount of drug needed to exert the particular effects. Cross-tolerance is a phenomenon where the tolerance for a particular drug effect operates for another drug effect as well. It is demonstrated by the diminished anticonvulsant effects of the barbiturates in people with chronic alcohol use. Both changes in cellular physiology and behavioral conditioning systems have been postulated as underlying mechanisms for the development of tolerance.

Physical dependence refers to the condition where withdrawal symptoms emerge upon discontinuation of the drug. Withdrawal symptoms are specific to different drugs and quite unpleasant, so that continued use is sought to avoid them. Most withdrawal symptoms are separate from the ones in the intoxication state and can be identified without difficulty.

5.3 Endocrinological And Metabolic

Most antipsychotics elevate serum prolactin secondary to the blockade of dopamine. Increased prolactin may cause menstrual irregularities in females, gynecomastia (abnormal enlargement of the breast) in males, and galactorrhea (spontaneous milk flow) in both females and males. Amenorrhea (complete cessation of menses) occurs frequently in women taking antipsychotics. These changes persist with treatment and resolve with discontinuation. Galactorrhea and amenorrhea may also be observed with tricyclic antidepressants.

Hypothyroidism (decreased function of the thyroid gland) may be associated with long-term lithium therapy. The elderly and females are at greater risk for lithium-induced hypothyroidism. Weight gain is a common side effect of antipsychotics, particularly of new generations (clozapine, olanzapine, risperidone, sertindole, quetiapine), cyclic antidepressants, MAOIs, and SSRIs. Impact of weight gain on general health in the long run remains to be determined. In contrast, stimulants (amphetamine, dextroamphetamine, methylpenidate), and certain SSRIs are associated with appetite suppression and weight reduction. Stimulants are also associated with adverse growth effects (height and weight suppression); however, these effects are compensated with drug holidays.

5.4 Insomnia

Insomnia is the most common transient side effect of stimulants and MAOIs.

5.5 Neurological Behavioral

5.5.1 Cognitive Effects. Even though the motor and cognitive functions of the brain do not operate independently from each other, specific neuropsychological tests that capture primarily motor or cognitive functions have been applied to measure the effects of psychoactive drugs in these domains. While some studies of conventional antipsychotics showed worsening performance on psychomotor speed, attention, and working memory, recent publications do not support a significant worsening in working memory, but even indicate improvements in some attentional measures (Goldberg and Weinberger 1996). The only double-blind study comparing the new generation antipsychotic clozapine and the conventional antipsychotic haloperidol revealed a significant interaction on measures of executive attention and visualspatial functions. Further analysis revealed that these effects resulted from worsening performance of the haloperidol treated patients. Patients treated with clozapine showed an insignificant improvement (Buchanan et al. 1994). Anticholinergic doses have been associated with poor verbal learning, verbal fluency, and motor speed. Lithium may also interfere with memory and motor speed functions. Benzodiazepines may cause slowed cognitive function, impaired memory, and behavioral disinhibition.

5.5.2 Motor Effects. Conventional antipsychotic drugs (haloperidol, fluphenazine), and to a lesser extent, new generation antipsychotic drugs (risperidone, olanzapine), some of the selective serotonin reuptake inhibitors (sertraline, fluoxetine), and cyclic antidepressants (amoxapine) affect motor functions of the extrapyramidal system. Acute conventional antipsychotic treatment interferes with simple repetitive motor tasks such as finger tapping. These effects are related to the drugs’ dopamine blocking properties in the basal ganglia. Lithium and valproic acid may cause hand tremors. Stimulant use may be associated with development or worsening of tics.

Acute motor effects of the conventional antipsychotics include parkinsonism, dystonic reactions, and akathisia. The major chronic effect of antipsychotic use is tardive dyskinesia. Parkinsonism is a word derived from Parkinson’s Disease, which is characterized by tremor, rigidity, and bradykinesia (slowed movement). All three features are observed in susceptible patients in the initial phases of treatment. Tremor with a regular rate may be observed in the hands and feet, and is present at rest. Tremor around the mouth also occurs. Akinesia (absence of movement) of the facial muscles sometimes lead to lack of expression which is known as masked face. Patients walk slowly, sometimes with shuffling, short steps, and the normal arm swing is diminished. Rigidity of muscles can be felt on examination; cogwheeling (increased tone in all directions of movement and superimposed ratchet-like resistance) may be elicited. Handwriting is characteristically small and tremulous.

One of the most disturbing side effects of antipsychotic medications (mostly of the high-potency conventional ones and some of the new generation antipsychotics) is akathisia, a subjective experience of motor restlessness. Patients complain of not being able to sit still, they pace in hallways, constantly move their legs to help the discomfort. They describe it as ‘… I want to run a hundred miles …’ Significant akathisia may lead to insomnia because of having trouble lying in bed. It may be accompanied by a feeling of anxiety and agitation. Restlessness and agitation are frequently observed as part of psychosis in the absence of any drug treatment. Drug-induced akathisia therefore is very important to diagnose differentially for appropriate treatment. If it is mistaken as psychosisrelated agitation, increased antipsychotic drug dose will only make it worse. Akathisia has been identified as a predictor of antipsychotic noncompliance. Several treatment options are available.

Acute dystonic reaction is another side effect of the conventional antipsychotics that requires immediate treatment. Dystonic reactions consist of abruptly developing muscle contractions which frequently involve the muscles of the face, tongue (protrusions, twisting), neck (spasmodic torticollis), jaw (trismus), eyes (oculogyric crisis, blephoraspasm), and limbs. It is most common in young men in the initial phases of treatment. It is treatable with anticholinergic and antihistamine drugs. Prophylactic treatment with these drugs may increase the chances of compliance.

Tardive dyskinesia is a long-term side effect of conventional antipsychotics characterized by involuntary choreiform (random, brisk) or athetoid (slow, regular continuing twisting) movements of the head, face, tongue, limbs, and the trunk. These movements may range from mild and unrecognized to severe and incapacitating. Movements around the mouth are the most common. Dyskinesia may be exacerbated with stress and disappears with sleep. About 10–20 percent of patients treated with conventional antipsychotics for more than a year develop tardive dyskinesia. Children, women, the elderly, patients with brain damage or mood disorders constitute high-risk groups. While tardive dyskinesia is associated with antipsychotic use, 1–5 percent of patients with schizophrenia who lived before the antipsychotic era have been reported to exhibit similar dyskinetic movements. Thus, tardive dyskinesia may be related to the pathophysiology of schizophrenia. The new generation antipsychotics (clozapine, olanzapine, risperidone, quetiapine) have significantly lower incidence of extrapyramidal system side effects and tardive dyskinesia compared to the conventional antipsychotics. This is a feature of the new generation antipsychotics that distinguish them from the conventional antipsychotics. Numerous animal studies have demonstrated that clozapine fails to induce extrapyramidal system related movements, and it is the only antipsychotic that might have a potential to prevent tardive dyskinesia from deteriorating.

5.5.3 Sedation. Sedation is a common side effect with most antipsychotics, mood stabilizers, benzodiazepines, barbiturates, and antidepressants (tertiary amine cyclic antidepressants, MAOIs, trazodone, sometimes with other SSRIs, venlafaxine, and nefazodone). In particular clinical situations, such as severe agitation, sedation may be desirable, whereas in others such as a negative symptoms of schizophrenia (affective flattening, lack of spontaneous speech, avolition), or depression with hypersomnia, it would not be. The choice of drug therefore largely depends on the clinical necessity. In undesirable conditions (night time dosing, reduction in dose) switching to a less sedating medication is considered.

5.5.4 Seizure. Antipsychotic drugs, particularly the ones with low potency reduce the seizure threshold. In a patient with no history of seizure disorder, incidence is low and no prophylactic treatment is warranted. Patients with a history of seizure disorder deserve special consideration. Clozapine increases risk of seizures in a dose-related fashion. Anticonvulsants such as valproic acid can benefit the patient to continue treatment with clozapine. Among the antidepressants, clomipramine and amoxapine may lower the seizure threshold while incidence of seizures with SSRIs is low, but present. Tricyclic antidepressants, MAOIs, anticonvulsants, lithium, and antipsychotics may also induce myoclonic (irregular rapid muscle contraction) movements.

5.5.5 Hypomania Mania. Even though it remains controversial, one of the important side effects of antidepressant treatment is the induction of hypomania mania. In a patient with no history of mania, undergoing antidepressant treatment, emergence of manic features merits consideration of the possibility of drug-induced mania. In patients with bipolar disorder, on the other hand, the risk of mania induction with sole antidepressant (in the absence of a mood stabilizer) treatment is established.

5.5.6 Delirium. Infrequently, worsening of psychosis, confusion, and agitation may occur with antipsychotic treatment. Most cases are, however, associated with concomitant anticholinergic use.

5.5.7 Neuroleptic Malignant Syndrome. This is a potentially life-threatening complication of the antipsychotic treatment characterized by muscle rigidity, hyperthermia, mental state changes (stupor, agitation, confusion), and autonomic dysfunction (blood pressure instability, increased pulse, respiration, sweating). The incidence is about 0.1 percent of patients exposed to conventional antipsychotics. High-potency antipsychotics may have a higher risk than low-potency antipsychotics, even though rarely it has also been reported with clozapine. Rhabdomyolysis (muscle necrosis) may occur that leads to myoglobinuria (passing a muscle-related protein— myoglobin—in urine) and subsequent renal failure. Mortality may approach 12 percent. Immediate intervention is necessary.

5.6 Placebo Effects

A placebo is a pharmacologically inactive agent administered in a group of patients in a double-blind clinical trial to improve the true estimate of the active agents efficacy and side effects. Placebo effects may be relevant to the concept of side effects from the perspective of experiences of drug effects in the absence of drug action. Substantial evidence suggests emergence of physiological changes associated with placebo administration. While placebo drug efficacy approaches significant percentage of patients in some clinical trials, incidences of side effects are also variably present.

5.7 Sexual

In males impotence, decreased libido, changes in quality of orgasm, priapism (painful erection), and erectile and ejaculatory disturbances have been reported with antipsychotic use. In women orgasmic dysfunction and decreased libido are frequently observed with antipsychotic treatment. Sexual dysfunction associated with SSRI use impairs quality of life, and is a reason for noncompliance. Buproprion and nefazodone may have a more favorable profile compared to TCAs, MAOIs, and venlafaxine. In contrast, some antidepressants are prescribed for the treatment of premature ejaculation.

6. Quality Of Life And Side Effects

The World Health Organization has defined Quality of Life as:

‘An individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. It is a broad ranging concept incorporating in a complex way the person’s physical health, psychological state, level of independence, social relationships, personal beliefs and their relationship to salient features of the environment’ (WHOQOL 1995).

This definition emphasizes a comprehensive approach in the assessment of quality of life. Disciplines of medicine, particularly cancer research have concentrated on global measures of quality of life, as symptom improvement by itself does not account for it. In psychiatry, the slow pace of research in this area may be due to difficulties of valid and reliable quality of life assessments from psychiatric patients. Pioneered by Lehman (Lehman et al. 1982), renewed interest has led to research in debilitating psychiatric disorders such as schizophrenia and demonstrated the significance of a multidisciplinary treatment model. While the strongest predictor of symptom improvement is identified as compliance with recommended drugs, its sole impact on quality of life in the long term is yet to be elucidated. The issue gets complicated due to the side effect profile of psychoactive drugs, which may mimic the symptoms of diseases, and also due to the direct impact of side effects on quality of life. For patients with schizophrenia, symptoms, their severity, and subjective distress caused by side effects accounted for half the variance in quality of life (Awad et al. 1997).

In one study where 53 schizophrenic outpatients treated with depot neuroleptics were studied, 70 percent complained about side effects when 94 percent were found to experience them. Among the patients who denied having side effects, 87 percent had some form of it (Larsen and Gerlach 1996).

The recognition of the negative impact of tardive dyskinesia on, for instance, patients’ self esteem, incapacity, and perception by society has been essential towards targeting more favorable treatments. The introduction of new generation psychoactive drugs, particularly antidepressants and antipsychotics is therefore encouraging. Such drugs have not only led to superior efficacy, but also have more favorable side effect profiles. However, there remains significant room for further improvement in side effect profiles of psychoactive drugs.

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