Adjunctive Pharmacotherapy and Related Issues

By | February 4, 2015

Managing antipsychotic side effects. Antipsychotic drugs produce problematic side effects in many individuals (see Table Side Effects of Typical Antipsychotic Drugs). A major category of side effects results from neurotransmitter dysregulation of the extra-pyramidal motor system. It is thought that these side effects are the result of an imbalance of dopaminergic and acetylcholinergic activity in subcortical motor control systems, brought about by the selective blockade of dopamine. Simultaneous blockade of acetylcholine can relieve these symptoms in most cases. The anticholinergic agents trihexyphenidyl (Artane) and benztropine (Cogentin) are most commonly used for this purpose.

Table Side Effects of Typical Antipsychotic Drugs

Drug Type of symptom
Sedating Autonomic Extrapyramidal
Fluphenazine + + + + +
Perphenazine + + + + +/+ + +
Trifluoperazine + + + + + +
Mesoridazine + + + + + +
Thioridazine + + + + + + +
Acetophenazine + + + + +/+ + +
Chlorpromazine + + + + + + + +
Triflupromazine + + + + +/+ + + + +
Haloperidol + + + + +
Thiothixene + + + + +
Chlorprothixene + + + + + + +/+ + +
Molindone + + + +
Loxapine + + +/+ + + +/+ + +

Note. Plus signs represent semiquantitative estimates of the degree of side effects based on the available, relatively limited literature. Slashes represent ambiguity.

A subcategory of side effects are Parkinsonian, so named because they mimic the symptoms of Parkinson’s disease. These include suppression of facial motility (fixed facies), disruption of postural reflexes resulting in a shuffling gait and loss of balance, tremor, and muscle stiffness.

Other extrapyramidal side effects of neuroleptics include torticollis and oculogyrus, spasmlike contractions of the neck and eye muscles, respectively. These can be particularly frightening but are readily observable and usually respond quickly to anticholinergic treatment or change of antipsychotic. A related side effect is akathisia. Unlike the motor side effects, akathisia is primarily a subjective experience of agitation and restlessness, sometimes observable as motor restlessness or persistent irritability. It is often difficult to detect, partly because it is primarily subjective (and people with schizophrenia may have particular difficulty in reporting a purely subjective experience) and partly because it tends to appear several days to 2 weeks after initiating neuroleptics, after clinical vigilance for side effects has dissipated. Akathisia is extremely aversive and thought to be a major cause of drug nonadherence. It can usually be controlled adequately with anticholinergics. Its incidence with atypicals appears to be low, but this is not a reason for relaxing vigilance.

There is substantial evidence that anticholinergic agents can themselves produce cognitive impairments, especially in memory. For this reason, it is considered desirable to keep anticholinergic treatment to a minimum (and antipsychotics themselves have anticholinergic properties, to varying degrees). An alternative to anticholinergic treatment of side effects is the selective dopamine agonist amantadine (Symmetril). Amantadine increases dopamine activity in motor systems without necessarily affecting the other dopamine systems, allowing effective control of Parkinsonian symptoms in some individuals. However, it is considerably more costly than anticholinergics, and in many individuals its dopamine agonism is not selective enough to avoid exacerbation of psychotic symptoms. Most of the atypical antipsychotics produce fewer side effects, requiring little or no adjunctive treatment.

The D2 blocking properties of neuroleptics cause an increase in blood prolactin levels, by way of a hypothalamic dopaminergic pathway that normally inhibits lactation. This sometimes produces gynecomastia (swelling of breast tissue, predominantly in males) and galactorrhea (expression of breast milk, predominantly in females). This is usually managed by switching to another an tipsy chotic. The atypicals, with less D2 blocking activity, are less likely to cause this problem.

Neuroleptic malignant syndrome is a rare but potentially lethal side effect involving the disruption of hypothalamic mechanisms that regulate body temperature. Symptoms include fever, diaphoresis, autonomic instability (fluctuations in blood pressure and heart rate), elevated WBC count, and compromised kidney function (indicated by elevated blood levels of serum creatinine). There is some evidence that as many as 12% of people on neuroleptics experience a mild, subclinical form of this syndrome. The malignant form is associated with high doses, high-potency agents, and intramuscular administration. It usually appears within 2 weeks of starting treatment, but it can appear at any time. It is managed by carefully observing recipients when they are started on a new anti-psychotic and discontinuing it immediately if the symptoms occur. Dopamine blockade is thought to be a proximal cause of neuroleptic malignant syndrome, and dopamine agonists such as bromocriptine are sometimes recommended for acute treatment. neuroleptic malignant syndrome is a medical emergency and is generally managed in intensive care settings.

Side effects that are encountered with both typicals and atypicals include significant weight gain and a lowered seizure threshold. Management of these side effects must be based on case-by-case assessment of the relative advantages of switching antipsychotic versus adjunctive treatment. Weight gain is less likely when administering clozapine when quetiapine is also taken.

Tardive dyskinesia is a serious, potentially irreversible side effect of protracted use of antipsychotics. Its symptoms are spasmodic contraction of muscle groups: mostly oral, facial, and lingual muscles in the early stages, and the entire torso in later stages. It can be reliably detected in its early stages by physical examination. Dangerously common for typicals, it is thought to be rare for atypicals and thought not to occur at all with clozapine. The American Psychiatric Association has acknowledged that tardive dyskinesia is an iatrogenic condition caused by antipsychotic drug treatment and has published a detailed protocol for early detection of and response to tardive dyskinesia. Management of tardive dyskinesia may involve a difficult choice between control of psychosis and tardive dyskinesia symptoms, but early detection preserves some degrees of freedom in the decision process. As with all such decisions, the involvement of the identified patient and family is of paramount importance.

As previously mentioned, agranulocytosis is a potentially lethal side effect, extremely rare but thought to be less rare for clozapine, affecting 1%-2% of the recipients of that drug. This risk has been a major factor in weighing the advantages of clozapine’s superior antipsychotic capabilities and lack of risk for tardive dyskinesia. Use of clozapine requires strict adherence to a regimen of WBC counts, weekly at first and biweekly after 6 months (80% of cases occur within the first 18 weeks). A sudden drop in the WBC counts demands immediate discontinuation of the drug (Agranulocytosis is not to be confused with benign leukopenia, a milder suppression of WBCs that is occasionally related to use of low-potency agents such as chlorpromazine. Clozapine also may also produce benign leukopenia, so WBC counts must be carefully interpreted).

Adjunctive treatment of affective and psychophysiological dysregulation. There is some evidence that agents normally used to enhance affective regulation and control seizures, including clonazepam (Klonopin), car-bamazepine (Tegretol), and valproic acid (divalproex sodium, Depakote), among others, can enhance the effects of antipsychotics. It would be logical to expect that this enhancement is best when the clinical picture includes affective dysregulation closely associated with psychotic symptomatology, as in schizoaffective disorder and borderline personality disorder co-occurring with schizophrenia. However, there is insufficient experimental evidence to allow a confident conclusion about this. For an individual case, there may be sufficient evidence to justify a controlled clinical trial of an adjunctive affective regulation agent when satisfactory symptom control and stabilization cannot be achieved with antipsychotics alone. However, psychosocial interventions may also contribute to affective stabilization, and this should be weighed against the disadvantages of a more complex drug regimen. The implicit message to the recipient often is that drugs are preferable to skills as a means of managing one’s emotional life. It is necessary to provide an educational intervention that will counteract this message.

Extreme caution is indicated in using anticonvulsants with antipsychotics. Carbamazepine and possibly also clonazepam may suppress bone marrow function, exacerbating the potential effects of neuroleptics and clozapine. Lithium is sometimes used in conjunction with neuroleptics (the evidence that lithium enhances antipsychotic effects on schizophrenic symptoms is weak, but it may be used for co-occurring manic symptoms), and this may increase the risk of neuroleptic malignant syndrome.

Adjunctive treatment of negative and deficit symptoms. Negative and deficit symptoms are still a persistent problem in treatment and rehabilitation of schizophrenia, even though the atypicals may be more effective in this regard. The discovery that D2 blockade is not the sole mechanism of the antipsychotic effect, and the realization that people with schizophrenia may also have other psychiatric problems, such as depression, has spurred exploration of alternative pharmacological approaches.

Nontricyclic antidepressants appear to have some efficacy in reducing negative symptoms, which is not surprising, considering the similarity between negative symptoms and depressive symptoms. The efficacy of atypicals for negative symptoms is probably related to their efficacy for neurocognitive impairments. The same might be logically expected of antidepressants, but that has not been experimentally demonstrated. Research in this domain has only just begun, and the next few years may see some significant advances.

Treatment of depression co-occurring with schizophrenia. Depressive signs sometimes occur with schizophrenia and can be effectively treated with antidepressant drugs. CBT or interpersonal psychotherapy are logical alternatives, but there has not been systematic study of this possibility. Considering the greater safety of the nontricyclic antidepressants and their efficacy for reducing negative symptoms, they are probably the best first choice for treating depression in schizophrenia pharmacologically. One of the newer atypical antipsychotics, olanzapine, appears to be effective in treating depressive symptoms.

Adjunctive treatment of anxiety and agitation. Anxiety often accompanies schizophrenic symptomatology, and this causes an understandable desire among many clinicians to treat the anxiety directly with pharmacotherapy. In addition, psychotic relapses are usually preceded by increases in anxious and depressive symptoms, before the appearance of acute schizophrenic symptoms. Anxiolytics have been recommended as an adjunct to antipsychotics for emergency treatment of extreme agitation in schizophrenia, although the potential disinhibiting effects of anxiolytics demand caution. The efficacy of chronic anxiolytic treatment has never been supported. As with affective regulation, the value of pharmacological treatment of problems that may be more effectively addressed with psychosocial treatment should be carefully weighed.