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(For a powerpoint slide show on antipsychotic agents, click here.)
Pharmacologic agents (aka "drugs") used in the clinical practice of psychiatry can be understood as belonging to one of several classes:
1. Antipsychotics
2. Antiparkinsonian agents
3. Antidepressants
4. Mood stabilizers/Anti-manic agents
5. Antianxiety agents
1. Antipsychotics: (aka neuroleptics and "major tranquilizers")
Commonly used antipsychotic agents include haloperidol (Haldol), trifluoperazine (Stelazine) and thioridazine (Mellaril). It is important to recognize that these drugs have the following properties, among others, in varying degrees:
Antidopaminergic
Anticholinergic
Antihistaminic
Anti-alpha1
Their therapeutic effects appear to be exerted primarily by means of their dopamine receptor blocking action, specifically at the D2 family of receptors. Generally, it has been found that the therapeutic potency of antipsychotic drugs parallels their affinity for the D2 receptor site; their interaction with the D1 site is more variable. It should be borne in mind that in Parkinson's disease, it is the D2 receptor which is involved in the therapeutic response to dopaminergic agonists; hence both therapeutic potency and iatrogenic parkinsonism will tend to correllate in a parallel fashion with the D2 binding affinity of antipsychotic drugs. Clozapine (Clozaril) is an exception and represents a new class of antipsychotics with significant action at the serotonin receptor; this may have therapeutic importance. Clozapine is also different in that it has relatively weak, and roughly equivalent, effects at both D1 and D2 receptors. The significance of this is not yet fully understood, but probably accounts for the apparent absence of iatrogenic parkinsonism and other so-called "extra-pyramidal" effects from the side-effect profile of clozapine. In therapeutic doses, clozapine (and similar so-called "atypical antipsychotics") typically occupies only about 40 - 50% of available D2 receptors in the striatum. Greater than 65% occupancy is required for the emergence of parkinsonian symptoms. With the exception of clozapine, the effects other than D2 blocking potency in currently available drugs of this class are generally considered to be "side effects," either to be avoided or exploited, depending upon the clinical circumstances. For example, drugs, such as thioridazine, which have strong antihistaminic effects, are sedating, and this can be valuable for some patients who suffer from insomnia. Anti-alpha1 effects, on the other hand, are potentially dangerous as they can result in orthostatic hypotension and falls (Chlopromazine/Thorazine is probably the most notorious offender in this respect.) It is important to recognize that the potency of different drugs in each of these properties varies along a continuum, and follows certain rules, which can be represented graphically thus:
Antidopaminergic potency
haloperidol (Haldol) > trifluoperazine (Stelazine) > thioridazine Mellaril)
Anticholinergic/Antihistaminic potency
thioridazine (Mellaril) > trifluoperazine (Stelazine) > haloperidol (Haldol)
Anti-alpha1 potency
thioridazine (Mellaril) > haloperidol (Haldol) > trifluoperazine (Stelazine)
Notice that haloperidol (and several similar "high-potency neuroleptics") is strongly antidopaminergic but relatively weak in its other receptor interactions. Although relatively free of anticholinergic, cardiovascular and sedative effects, it will tend to produce dystonia and pseudoparkinsonian syndromes frequently.
Note that clozapine has a unique side-effect profile; it appears to be free of extra-pyramidal motor effects (apparently including tardive dyskinesia) but can cause significant orthostatic hypotension, seizures (5% per year) and agranulocytosis (1% per year), necessitating close monitoring of hematologic parameters (CBC). Several new atypicals, risperidone (Risperdal), olanzepine (Zyprexa) and quetipine (Seroquel) appear to have many of the advantages of clozapine, but without the risk of agranulocytosis that has complicated the use of clozapine. It should also be noted that both clozapine, risperidone, olanzepine and quetiapine are all strong 5HT-2 (serotonin-2) receptor antagonists. This particular effect may account for their superior effect in reducing the so-called "negative symptoms" (emotional blunting, apathy, social withdrawal) of schizophreniform psychoses. Risperidone (Risperdal) is classified as an atypical neuroleptic, but it is unique among the atypicals in that it can induce persistent hyperprolactinemia (like typical neuroleptics) and frequently causes parkisonian side effects in higher doses (greater than 6 mg per day).
2. Antiparkinsonian agents:
Antidopaminergic compounds (D2 antagonists) tend to produce dystonic and parkinsonian-type effects due to their effects on the nigro-striatal pathways of the extra-pyramidal motor system, specifically through their blockade of D2 receptors. The less potent compound do this less often, primarily because they also have stronger anticholinergic properties. (Again, clozapine and the other atypicals appear to be exceptions to this rule, possibly because their effects are relatively weaker and equivalent at the D2 and D1 receptors.) The dopaminergic and the cholinergic pathways appear to have a reciprocal relationship in the extrapyramidal motor system; hence, antidopaminergic drugs or idiopathic loss of dopaminergic neurons can produce a bradykinetic, parkinsonian syndrome which can be at least partially relieved with anticholinergic drugs (or dopamine agonists). (Likewise, inherited, degenerative loss of cholinergic neurons in Huntington's disease causes choreiaform movements - as well as dementia and psychotic symptoms - due to unopposed dopamine in the striatum; some benefits can be achieved with antidopaminergic drugs with this condition.) Drugs such as diphenhydramine (Benadryl), benztropine (Cogentin) and trihexylphenidyl (Artane) are all anticholinergic compounds and are frequently used to alleviate the dystonic and parkinsonian effects of neuroleptics. Occaisionally, some clinicians will use amantadine (Symmetryl), which is a dopamine agonist, for these symptoms.
3. Antidepressants:
Like antipsychotics, drugs which belong to the class of antidepressants, in particular the so-called "tricyclic" or "heterocyclic" antidepressants, typically have effects at multiple receptors. And like their counterparts among the antipsychotics, they can be arranged along a gradient of receptor activity:
Anticholinergic/Antihistaminic/Anti-alpha potency
amitryptiline (Elavil) > nortryptiline (Pamelor) > desipramine (Norpramin)
Serotonin/Norepinephrine reuptake blocking potency
amitryptiline (Elavil) > nortryptiline (Pamelor) > desipramine (Norpramin)
Norepinephrine/Serotonin reuptake blocking potency
desipramine (Norpramin) > nortryptiline (Pamelor) > amitryptiline (Elavil)
As indicated above, those drugs which have the highest Serotonin/Norepinephrine reuptake blocking ratio tend to be the most anti-cholinergic/histaminic/alpha, wherereas those which have the highest Norepinephrine/Serotonin reuptake blocking ratio tend to be less potent at these other receptors. All of the tricyclics have the so-called "quinidine-like" effect (conduction-delaying), more or less equally so, and all should be considered relatively contraindicated in the face of a second degree heart block or greater due to their tendency to delay cardiac conduction. (If used in such patients at all, they should be used only in conjuction with cardiologic consultation, and close cardiac monitoring.) In fact, it is the lack of this particular effect (as well as the relative absence of anticholinergic effects) that makes the newer, "second-generation" antidepressants so valuable. These include bupropion (Wellbutrin) as well as the SSRI's (selective serotonin reuptake inhibitors) - fluoxetine (Prozac), sertraline (Zoloft), paroxitine (Paxil) and fluvoxamine (Luvox). Bupropion is unusual among antidepressants in that it appears to exert a primarily pro-dopaminergic effect in the CNS. The SSRI’s, of course, appear to exercise their therapeutic effects by means of the enhancement of serotonergic neurotransmission. Other compounds which are particularly important for the treatment of treatment-refractory patients include nefazadone (Serzone) and venlafaxine (Effexor). Serzone is chemically related to trazodone (Deseryl), and shares with it 5HT-2 antagonism. It can be especially beneficial in cases of antidepressant-induced sexual side effects (decreased libido, etc.). Nefazodone tends to cause these kinds of side effects much less often and compliance will be enhanced in those patients for whom sexual side effects are not well tolerated. Venlafaxine combines both serotonin and norepinephrine reuptake inhibition, but unlike the TCA's, is relatively free of anticholinergic activity. It appears to have a more rapid onset of action, particularly when given in high doses. Increased response correlates with increased dose of venlafaxine and it has been safely given in doses up to 400mg/day (manufacturer recommends no more than 375mg/day). It should be given in divided doses (BID) because of its relatively short half-life. One of the newer compounds available for use in the treatment of depression is mirtazepine (Remeron), which has an unusual mechanism of action (enhanced noradrenergic/serotonergic activity through alpha-2 antagonism), but is relatively free of side effects with the exception of antihistamine-mediated sedation. The common side effects of SSRI’s appear to be diminished as a result of 5HT2 and 5HT3 anatgonism. It should be noted that virtually all antidepressants will tend to induce weight gain, either as a result of anti-histamine or other less well understood effects. This can frequently be a problem for patients and a source of non-compliance.
A less commonly used group of antidepressants are the monoamine oxidase inhibitors, or MAOI's, which enhance the availability of norepinephrine, serotonin and other monoamines within the neural synapse by inhibiting their oxidative metabolism. Phenelzine (Nardil) is a commonly used member of this class. These drugs have been found to be particularly useful for panic disorder, as well as for depressive syndromes. Most clinically available MAOI's have some effect at both the MAO-A and MAO-B subtypes of the enzyme and oxidation of the pressor amine tyramine will be inhibited as well. Tyramine can accumulate to toxic levels when absorbed from certain dietary sources, such as Chianti wines and aged cheeses, in patients who are taking MAOI's, and for this reason they must receive and follow careful dietary instructions and avoid tyramine sources. They can also have toxic reactions (severe, malignant hypertension) to exogenously admistered pressor amines (including OTC cold preparations). Serious drug interactions can occur between MAOI's and cyclic antidepressants, including SSRI's. Finally, there is an idiosyncratic and potentially lethal interaction between MAOI's and meperidine (Demerol). When used alone, the most serious common side effect of MAOI's is severe orthostatic hypotension resulting in falls. For these reasons, many clinicians prefer to avoid using members of this class of drugs, at least routinely.
Methyphenidate (Ritalin) belongs to the class of sympathomimetic stimulants, which stimulate the release of catecholamines (norepinephrine and dopamine) and is frequently used for its attention-enhancing properties in management of attention-deficit disorder in children and, now increasingly, in adults (both dextroamphetamine and methamphetamine can be used for this purpose as well.) Stimulants have also been used successfully for the treatment of depression, particularly for the elderly, debilitated cardiac or stroke patient; they appear to have little in the way of cardiac side effects. Alprazolam (Xanax) belongs to the class of triazolobenzodiazepines and differs from the benzodiazepines in having antidepressant properties as well as antianxiety (particularly antipanic) effects. It has become notorious for inducing dependency. This may not be a unique effect of Xanax, but simply a result of its rapid onset of action ("buzz") and very short half-life ("crash") which result in strongly reinforcing cycles of use.
4. Mood Stabilizers/Anti-Manic Agents:
Mood stabilizers are those drugs which have been found empirically to be useful in controlling cycling mood disorders (i.e., Bipolar Disorder). The prototype of this class is Lithium (Lithobid), which is commonly used as the first-line drug in the treatment and prophylaxis of Bipolar disorder. A substantial number (perhaps 30% or more) of bipolar patients will have less than a satifactory result with Lithium salts (carbonate or, less commonly, citrate) and will then be treated with an anti-convulsant, such as carbamazepine (Tegretol) or valproate (Depakote). Rapid cyclers may do better with anti-convulsants than with Lithium alone. Some of the newer anticonvulsants which have been used for some cases of treatment-refractory bipolar disorder include topiramate (Topamax), lamotrigine (Lamictal) and gabapentin (Neurontin). Recently good results have been obtained in some bipolar patients using calcium channel blockers such as nimodipine and isradepine.
5. Antianxiety Agents: (aka "minor tranquilizers")
The most commonly used antianxiety agents are the benzodiazepines. These drugs are functionally agonists of the GABA (gamma-aminobutyric acid) receptor. They facilitate binding of GABA to its receptor, which in turn leads to the opening of a neuronal membrane chloride channel and the subsequent hyperpolarization/inhibition of the target/post-synaptic neuron. The cerebral cortex receives diffuse input from GABA-ergic neurons and these can be thought of as bringing about widespread cortical inhibition when active. These drugs are sedating, anxiolytic, amnestic compounds which in high doses can lead to ataxia, discoordination and respiratory suppression. As neuronal inhibitors, they are effective anti-convulsants as well. These drugs can vary widely in their potency and half-life. As a general rule of thumb, one should try and avoid the use of the longer-acting benzodiazepines such as clonazepam (Klonopin) and flurazepam (Dalmane) in the elderly, as older patients tend to have particular difficulty with drug accumulation (due to altered pharmacokinetics) and over-sedation. On the other hand, with patients who have acquired physiologic dependency on benzodiazepines (this will tend to occur in most patients who take moderate-to-high doses for more than a few weeks), the short half-life drugs (lorazepam, oxazepam) tend to be poorly tolerated when doses are reduced or tapering is attempted, because the withdrawal is so acute. These patients should, if possible, be switched to longer acting drugs if an attempt at drug withdrawal is anticipated.
Another, newer group of antianxiety agents are the serotonergic agents (typically agonists or partial agonists/antagonists at the 5HT1a receptor subtype) such as buspirone (Buspar). These drugs have the advantage of not producing physiological dependence or of reinforcing drug-seeking behavior, but some clinicians have been disappointed in their therapeutic efficacy.
Although not FDA-approved for use in anxiety disorders, considerable experience is accumulating that shows significant benefit for some patients with anxiety who take beta-adrenergic antagonists ("beta-blockers") such as propranolol. Doses of 10-30 mg taken either prn (for performance anxiety) or tid-qid have been used successfully in treating anxious patients.
Barbiturates continue to be used by some physicians to treat anxiety or insominia; however, they have a very high lethality in overdose and so are probably best restricted to special circumstances, such as anesthesia and medicated interviews ("Amytal interviews"). Interestingly, they have been commonly prescribed for sedation by, because they are believed to be free of teratogenic effects.
Drug Interactions/Adverse Effects
Certain significant drug interactions have been noted above, such as the potentially lethal hypertensive interaction between MAOI's and meperidine (Demerol), pressor amines, OTC cold preparations and cyclic antidepressants. Although anesthesia can be provided to patients who are receiving MAOI's, with special precautions, in the past it has been recommended that MAOI's should be discontinued for 10 days prior to elective procedures due to the risk of serious interactions between MAOI's and pressor amines. MAOI's should not be combined with SSRI's, as this can result in a severe, potentially lethal, "serotonin syndrome," characterized by hyperthermia, shivering, rigidity and myoclonus (similar to and sometimes difficult to distinguish from malignant neuroleptic syndrome).
SSRI's can strongly inhibit the cytochrome P450-mediated oxidative metabolism of other drugs, resulting in significant increases in their plasma concentration. Specifically, these drugs inhibit most strongly the cytochrome P450-2D6 reductase isoenzyme; some inhibit 3A3/4 as well. Fluoxetine (Prozac), which has been the most studied because it is the longest used SSRI in the U.S. has been found to increase plasma levels of cyclic antidepressants, MAOI's, diazepam, carbamazepine, valproate, alprazolam, haloperidol, and possibly phenothiazine neuroleptics. Paroxitine (Paxil) has been found to increase the level of digoxin and cyclic antidepressants. Sertraline (Zoloft) has been shown to increase the level of warfarin (and increase prothrombin time). This effect may be more related to protein-binding displacement by sertraline. In general, the enzyme-inhibiting effects of sertraline appear to be relatively weak compared with Prozac and Paxil, but this may have been an consequence of the doses used. Care should be taken when combining SSRI's with certain antiarrythmics such as quinidine and flecainide which undergo oxidative hepatic metabolism and have a narrow therapeutic index. Drugs which inhibit 3A3/4 (such as erythromycin and ketoconazole) have also been found to increase serum levels of terfenadine (Seldane) and astemizole (Hismanal), resulting in malignant cardiac dysrythmias. For this reason nefazadone and SSRI’s in general should not be used in combination with these drugs.
Patients should be warned against the use of ethanol in combination with antidepressants. In addition to increased sedation, alcohol can acutely inhibit the oxidation of cyclic antidepressants, resulting in higher and more toxic levels, particularly after antidepressant overdose. Chronic use of ethanol will induce hepatic enzymes, leading to reduced (and possibly clinically ineffective) drug levels of antidepressants. Ethanol in combination with overdoses of benzodiazepines (usually relatively harmless in overdose by themselves) can be lethal (due to respiratory suppression and/or profound inhibition of gag-reflex followed by aspiration of vomitus). Ethanol also can increase the level of toxic acetaminophen (Tylenol) metabolites, resulting in hepatic necrosis. Patients should be warned about this.
Neuroleptic malignant syndrome is clinically very similar in appearance to malignant hyperthermia of anesthesia as well as a severe form of catatonia, commonly referred to as lethal catatonia. This condition is characterized by delirium, muscular rigidity, hyperthermia, hypertension, leukocytosis and elevated CPK. It is an idiosyncratic reaction to antipsychotics that often occurs in patients who are relatively dehydrated who have received very high doses of high potency neuroleptics. If suspected, antipsychotics should be immediately discontinued, and supportive care including aggressive hydration provided. unless the condition is very mild and self-limited, medical consultation should be sought. Intravenous dantrolene sodium, a muscle relaxant, and/or bromocriptine (Parlodel), a dopaminergic agonist, may be beneficial. In severe cases, which are refractory to more conservative medical interventions, ECT (electroconvulsive therapy) can, for unknown reasons, be life-saving.
There are a great many other potential drug-drug interactions which can occur when psychopharmacologic agents are used in combination or concommittantly with other non-psychiatric drugs. When treating medically ill patients, it is very important to bear in mind the possibility of such interactions and to consult an appropriate reference before prescribing. The Massachussetts General Hospital Handbook of General Hospital Psychiatry is one such resource. It is also helpful to bear in mind certain principles/concepts of pharmacokinetics which frequently account for adverse drug-drug interactions or other forms of toxicity in the medically ill:
absorption (delays in absorption can cause unpredictable increases in drug levels)
distribution (increased fat content in elderly results in decreased effective CNS concentrations of lipophilic drugs, greater volume of distribution, longer half-life)
metabolism (inhibition of P450 by cimetidine can increase drug levels; induction by carbamazepine can decrease drug levels, including its own)
elimination (the majority of psychopharmacologic agents are primarily eliminated by hepatic metabolism; a notable exception is lithium, which is not metabolized and is exclusively eliminated by renal mechanisms)
(updated 3/15/00)