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PubMed2006

Distribution of antidepressants between plasma and red blood cells.

OBJECTIVE: The distribution of different antidepressants between plasma and red blood cells (RBCs) or between water and erythrocyte membranes (ghosts) has not been sufficiently compared so far. MATERIALS AND METHODS: Distribution of seven antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, didesmethylimipramine, dothiepin, and citalopram) was measured in vitro in small volumes of blood or erythrocyte membrane suspension using radiolabeled drugs. Blood samples were taken from healthy subjects. RESULTS: The distribution of antidepressants between plasma and RBCs is strongly affected by temperature; however, it does not depend on the antidepressant concentration in the range of their therapeutic concentrations. The data analysis proved that the ratio of RBCs to plasma volume concentrations is the suitable parameter characterizing antidepressant distribution in whole blood. Significantly higher ratios of RBCs to plasma concentrations were found for demethylated metabolites of tricyclic antidepressants and in the case of citalopram. Citalopram showed the highest accumulation in intact RBCs and at the same time the lowest binding to isolated membranes. The binding of drugs to isolated erythrocyte membranes was much higher than in whole blood. CONCLUSION: The concentration ratio of antidepressant in RBCs and in plasma is sensitive not only to the binding properties of plasma proteins and cell membranes, but also to changes in drug molecule, both in aminopropyl chain and in aromatic rings. This ratio is to a large extent characteristic of a particular antidepressant.

Antidepressive Agents, Second-Generation↗

PubMed2006

[Treatment for irritable bowel syndrome--psychotropic drugs, antidepressants and so on].

Irritable bowel syndrome (IBS) is a functional disease with good prognosis, which is diagnosed by exclusion of possible causative organic diseases. However, since the patients tend to have strong psychotic symptoms including anxiety, tension, depression, irritation and insomnia, this syndrome has to be elucidated as a psychosomatic disease. Although the symptoms are usually limited to gastrointestinal symptoms such as abdominal pain and abnormal bowel movements, many patients also manifest some kinds of psychiatric abnormalities such as hypochondria, depression, hysteria, panic disorder and posttraumatic stress disorder. Especially, the prevalence of depression is high. Therefore, use of psychotropic drugs is efficient in treating IBS. Antidepressant agents including tricyclic agents such as amitriptyline, trimipramine, imipramine, clomipramine, amoxapine and nortriptyline; tetracyclic antidepressant; antidepressants such as SSRI and SNRI; sulpiride; benzodiazepine class anxiolytic agents; tandospirone; and Chinese herbal medicine are being used. IBS is a stress-related disease. Therefore, in spite of the importance of pharmacotherapy, patients should also be instructed to avoid the stress that aggravates the symptoms in all aspects of daily life.

Antidepressive Agents↗

PubMedDate not supplied

[Neuropsychiatric symptoms related to interferon alpha].

Neuropsychiatric symptoms are commonly related to interferon alpha treatment. The paper summarises the current knowledge about their aetiology, course, and treatment. Interferon alpha is a cytokine with antiviral and antineoplasmatic activity. It is commonly used in the treatment of chronic hepatitis C and B, malignant melanoma, Kaposi sarcoma, renal cancers, and some haematological malignancies. Treatment with interferon alpha is associated with depressive symptoms, cognitive disturbances, chronic fatigue syndrome, dysphoria, anxiety symptoms, anorexia, mania and psychotic states. Up to a half of the patients need psychiatric consultations, 10-25% of them need psychiatric treatment. Neuropsychiatric symptoms are the results of direct affection of CNS by interferon and induced cytokines. They increase hypothalamic-pituitary-adrenal (HPA) activity, alter thyroid function and lead to a behavioural syndrome called 'sickness behaviour'. Moreover interferon induces the activity of 2, 3 indoloamine dioxygenase, the enzyme which converts tryptophan into kynurenine, leads to a reduced level of tryptophan, and thus to a reduced level of central serotonin and to an increased level of neurotoxic kynurenine metabolites. Interferon also affects central opioid receptors and changes dopaminergic and noradrenergic neurotransmission. Serotonin selective reuptake inhibitors (SSRI), other antidepressants i.e. nortriptyline, benzodiazepines, naltrexone, and neuroleptics (for maniac and psychotic states) are used to treat interferon associated psychiatric symptoms. Psychological therapy may also be useful, as well as psychoeducation and behavioural interventions.

Antineoplastic Agents↗

PubMed1991

Dosage regimen design for cyclic antidepressants: a review of pharmacokinetic methods.

One of the difficulties in pharmacotherapy of depression is the frequent need to make several dosage titrations before reaching the optimal therapeutic dosage. This problem has led to several experimental approaches for predicting a stable antidepressant maintenance dose from plasma concentration data collected shortly following a test dose. The theoretical basis for these methods is reviewed along with the results of clinical trials. It is concluded that accurate steady-state concentrations of cyclic antidepressants can be predicted from kinetic analysis of plasma concentrations obtained early in therapy. The most applicable drug for prospective dosing methods is nortriptyline with its widely accepted therapeutic plasma concentration range. Other drugs that also have substantial evidence for predicting the optimal dose from an early point in therapy include desipramine and imipramine. Predictive dosing methods are easily applied in the inpatient setting. Multiple data points obtained between 12 and 48 hours after the first dose are likely to give accurate predictions and provide clinically useful information. More widespread application of predictive approaches to dosage regimen design of antidepressant pharmacotherapy may lead to reduced hospitalization and cost savings.

Antidepressive Agents, Tricyclic↗

PubMed1991

Is doxepin a safer tricyclic for the heart?

BACKGROUND: Many clinicians believe that doxepin is the safest tricyclic with respect to cardiovascular effects. This belief has persisted for two decades despite the absence of rigorous prospective evaluation. METHOD: To address this issue, the authors studied the cardiovascular effects of doxepin in 32 depressed patients with preexisting left ventricular impairment, ventricular arrhythmias, and/or conduction disease. RESULTS: Doxepin (1) did not have a robust effect on heart rate, (2) did not adversely affect left ventricular function, (3) did have a significant antiarrhythmic effect, (4) slowed cardiac conduction, and (5) caused a significant increase in orthostatic hypotension. Five (16%) of the 32 patients dropped out due to cardiovascular side effects. The overall dropout rate was 41%. CONCLUSIONS: The cardiovascular effects of doxepin in depressed patients with heart disease are comparable to those documented for imipramine and nortriptyline. Doxepin afforded no greater margin of cardiovascular safety; in fact, the drug was poorly tolerated by this patient population.

Aged↗

PubMed1991

Practical psychopharmacologic considerations in depression.

Of the antidepressants on the US market, only alprazolam and trazodone have questionable antidepressant efficacy. Because all other antidepressants are equally effective in major depressive illness, drugs are used based on particular patient characteristics matched with individual antidepressant drug profiles. In general, antidepressant plasma concentration monitoring is only clinically useful with some of the TCAs. Nortriptyline, imipramine, and desipramine have demonstrated the highest correlation between clinical response and plasma concentration. MAO inhibitors are useful but require a reliable patient who can comply with dietary restrictions. Maprotiline and amoxapine are not first- or second-line antidepressants. Clomipramine and fluoxetine offer unique properties that make them first- or second-line antidepressants for particular patients. There are significant drug interactions with antidepressants that should be avoided.

Antidepressive Agents↗

PubMed1991

Therapeutic drug monitoring for antidepressants: efficacy, safety, and cost effectiveness.

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is a cost-effective tool to increase efficacy and safety in patients suffering from major depressive illness. The concentration:antidepressant response relationships of nortriptyline, desipramine, and amitriptyline conform to a curvilinear relationship between concentration:antidepressant response; whereas, imipramine conforms to a linear relationship. Besides improving efficacy, TDM identifies the subset of patients who are at risk to develop excessive plasma TCA levels with potential resultant central nervous system and cardiovascular toxicity. Taking both the efficacy and safety data into account, cost:benefit analyses demonstrate that TDM is cost effective when used once as a standard aspect of care in the TCA treatment of patients with major depressive illness.

Age Factors↗

PubMed1990

[Antidepressive agents in the elderly].

Depressive disorders are the most common psychiatric illness in the elderly. All tricyclic antidepressants show comparable therapeutic efficacy, thus the choice of drug is based on their side effects profiles rather than on degree of therapeutic efficacy. The secondary amines nortriptyline and desipramine are drugs of choice for the elderly depressive patient because of their relatively mild side effects profile. New-generation antidepressants remain second choice. Patients suffering from a psychotic depression often require a combination of an antidepressant drug with an antipsychotic drug. Addition of lithium to a cyclic antidepressant can produce a rapid and lasting remission in patients with a major depressive disorder who do not respond to a cyclic antidepressant alone. Treatment with MAO-inhibitors or electroconvulsive therapy can also be considered in refractory cases.

Aged↗

PubMed1990

Inhibited female orgasm resulting from psychotropic drugs. A five-year, updated, clinical review.

As of 1989, the psychotropic drugs that have been reported to inhibit female orgasm include antipsychotic agents (thioridazine, trifluoperazine and fluphenazine), the combination drug perphenazine/amitriptyline, antidepressants (phenelzine, isocarboxazid, tranylcypromine, amoxapine, clomipramine, imipramine, nortriptyline and desipramine) and anxiolytic agents (diazepam, flurazepam and alprazolam). The management of psychotropic-drug-induced female anorgasmia includes discontinuation of the offending drug, reduction of the dosage level, a wait for spontaneous remission while the patient remains on the agent and substitution of another medication. The use of bethanechol chloride and cyproheptadine has been successful in resolving anorgasmia while patients continue to receive antidepressants.

Female↗

PubMed1989

Tricyclic antidepressants in the treatment of poststroke depression.

Depression is a serious complication of stroke. Although tricyclic antidepressants have well-established efficacy in the treatment of functional depression, they are not often used to treat depression following stroke. Studies have identified two types of depression in patients following stroke: major depression and minor depression. Longitudinal studies indicate that untreated major depression may last about 1 year, whereas untreated minor depression may last more than 2 years. Patients with depression who are not treated with antidepressant medication have been found to do more poorly on several measures of physical and cognitive rehabilitation than depressed patients who are treated. Two double-blind drug treatment studies of depression following stroke have been done. Although adverse side effects were reported in both studies, serious side effects were no more common in the active drug group than in the placebo group. Both studies, however, reported significantly better outcome, measured by depression scores or activities of daily living, in patients treated with nortriptyline or trazodone than in placebo-treated controls. Thus, although the use of antidepressant medication requires caution, the recognition and treatment of depression in patients who have had a stroke may result in a significant enhancement of both physical and cognitive recovery as well as emotional state.

Antidepressive Agents, Tricyclic↗

PubMed1989

Therapeutic monitoring of treatment with antidepressants.

The present status of the relationship between blood plasma concentrations of tricyclic antidepressants and clinical outcome is reviewed. Plasma levels of imipramine, desmethylimipramine and nortriptyline are generally accepted as useful clinically but it is more difficult to establish a well-defined relationship between clomipramine and amitriptyline blood levels and clinical outcome. These assays are clinically relevant, particularly in cases of treatment failure, but also in the treatment of the elderly and of overdosage. The technical problems of the assay have practically been solved with the development of new analytic methods.

Antidepressive Agents, Tricyclic↗

PubMed1989

Treatment of affective illness in the elderly with drugs and electroconvulsive therapy.

Affective illness is common, frequently debilitating, and sometimes life-threatening in the elderly. Considerations pertaining to treatment with heterocyclic drugs, MAOIs, lithium, psychostimulants and thyroid hormone, as well as ECT, have been reviewed. Amitriptyline and imipramine cause significant orthostatic hypotension and probably should be avoided in the elderly. In addition, amitriptyline is extremely anticholinergic. Amoxapine is essentially a neuroleptic sequelae, including tardive dyskinesia. If a patient has had a prior positive response or has a relative who had a good outcome from a particular drug, it may be best to begin treatment with that drug. Initial choice of antidepressant can be based largely on the clinical picture. For example, if a depressed patient is sleeping much more than usual, try a potentially activating agent like desipramine or protriptyline. if, on the other hand, the patient is unable to sleep, a more sedating agent like nortriptyline, maprotiline, trimipramine, or trazodone should be tried. Risks and side effects of these drugs, as well as their use in cardiac patients, have been reviewed in detail. Many clinicians avoid MAOIs in elderly patients because of fear of adverse reactions. This fear is largely unfounded. Precautions, side effects, and specific recommendations have been outlined. Using lithium in the elderly requires special precautions because of decreased GFR and potential interactions with concomitantly used drugs. This paper has discussed possible side effects and toxicity. The usage of psychostimulants, such as methylphenidate and amphetamine, to treat medically ill depressed patients is reviewed. These agents are also sometimes useful in demented individuals or in patients with abulic frontal lobe syndromes. Poststroke depressions are common, and recent evidence indicates that they can be adequately treated. Stroke patients have many difficulties dealing with rehabilitation and should not be forced to suffer concomitant depression when we have the tools at hand to effectively treat such symptoms. Recent data on the potentiation of antidepressant effects by lithium or T3 indicate that they may be useful adjuvants in some tricyclic-resistant patients. Risks, side effects, and recent procedural advances in the use of ECT have been reviewed. Electroconvulsive therapy is both more effective and faster-acting than drugs in the treatment of depression. Many depressed elderly patients, especially those with psychotic symptoms, do not respond to drugs but improve with ECT.

Aged↗

PubMed1989

Obsessive-compulsive disorder as a 5-HT subsystem-related behavioural disorder.

Involvement of the brain serotonin (5-HT) neurotransmitter system in obsessive-compulsive disorder (OCD) was originally suggested on the basis of therapeutic effects found with the semiselective serotonin uptake inhibitor, clomipramine. More recent studies directly comparing clomipramine with non-selective or norepinephrine-selective uptake inhibitors, such as desipramine or nortriptyline, as well as studies with new, more selective serotonin uptake inhibitors, including fluvoxamine and fluoxetine, have supported that hypothesis. Clomipramine's antiobsessional effect has been augmented with the serotonin precursor, L-tryptophan, or with lithium, which has prominent serotonergic effects. Patients whose OCD symptoms improved on clomipramine worsened when the drug was discontinued (regardless of duration of therapy) and improved when clomipramine was reinstituted. OCD symptoms also worsened when metergoline, a 5-HT antagonist, was given to patients who had improved with clomipramine. Metergoline given alone had no effect. Administration of m-chlorophenylpiperazine (m-CPP), a 5-HT receptor agonist, to untreated OCD patients increased their anxiety, depression, and dysphoria, and exacerbated their OC symptoms. After 4 months of clomipramine therapy, m-CPP failed to produce the same behavioural effects, suggesting an alteration of a 5-HT subsystem (possibly downregulation of some 5-HT receptors). The data reviewed suggest an important role for an abnormal brain 5-HT subsystem in patients with OCD.

Brain↗

PubMed1989

High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data.

Eight patients are described who displayed excessive concentrations of nortriptyline, imipramine, or clomipramine on routine blood level monitoring. Under these conditions, the patients did not respond to the treatment. All patients were markedly improved when the daily dosage of the antidepressant was reduced with a simultaneous decrease of the blood concentrations. Among these eight patients, seven suffered from side-effects, three were characterized as poor hydroxylators of debrisoquine, while three had concomitant treatment with a phenothiazine.

Aged↗

PubMedDate not supplied

Amitriptyline metabolites in human urine. Identification of phenols, dihydrodiols, glycols, and ketones.

From the urine patients being treated with amitriptyline, drug metabolites were extracted by adsorption to polystyrene. Nonconjugated compounds and aglycones liberated by enzymic hydrolysis were purified separately by repeated TLC and characterized by physicochemical and chemical methods. Besides the known E- and Z-10-hydroxy derivatives of amitriptyline (AT), nortriptyline (NT), and their primary amine analogue, two isomeric 10,11-dihydroxy compounds could be identified in each series. Metabolites with an oxo function in position 10 occurred in minor quantities. The phenols 2-hydroxy-NT and 2,11-dihydroxy-NT, as well as the 1,2-dihydrodiol derived from NT, were regularly present, while the corresponding tertiary amines as well as 3-hydroxy-AT and -NT were detected occasionally in very small amounts.

Amitriptyline↗

PubMed1988

The effect of pirenzepine on the functions of human platelets.

Despite the very high chemical similarity of pirenzepine (P) to the selected tricyclic antidepressive drugs (TCAD) (imipramine, desimipramine, nortriptyline and amitriptyline), P has a distinctly different effect on platelets, in particular, on serotonin uptake and platelet aggregation. Using two groups of nine healthy volunteers, mean age 27.7 and 27.5 years, respectively, assessment of the two indicators in vitro helped us to eliminate the possibility of a drug induced defect of the two thrombocyte functions, i.e. their aggregation and serotonin uptake. There is therefore, no reason to fear the danger of decreased hemocoagulation in ulcer patients treated with P for gastrointestinal hemorrhage. The results obtained in vivo using two tests which showed the level of platelet activation associated with release of a specific platelet protein (beta-thromboglobulin in platelet-poor plasma) and malondialdehyde in thrombocyte-rich plasma ruled out any changes, specifically their increase, and have disproved any kind of stimulating activity of P on thrombocyte reactivity.

Adult↗

PubMed1988

Hydroxydesipramine in the elderly.

Elevation of the hydroxy metabolites of the tricyclic antidepressants in the elderly has been demonstrated for nortriptyline and suggested for desipramine by a study reporting elevated hydroxydesipramine (OH-DMI) plasma levels in four older patients. In the current study, patients treated with desipramine (DMI) were studied to determine whether OH-DMI was elevated in two larger samples of depressed elderly patients and to determine the magnitude of the increase, if present. In Sample I, which consisted of 68 patients of whom 23 were over 60 years of age, a fixed target dose of DMI was employed. Sample II, in which 20 of the 56 patients were over 60, received a dose adjusted to attain a fixed target DMI blood level. OH-DMI levels were higher in patients over 60 than in younger patients but the differences were not significant in either sample individually. In the two samples combined, average OH-DMI levels were 11 ng/ml higher in patients over 60 and the difference was significant (t = 2.30, p = 0.02). If variations in dose are accounted for, OH-DMI concentrations are positively correlated with age in both samples. OH-DMI/DMI ratios were not higher in the patients over 60 in these samples, but OH-DMI/DMI ratios may be higher in patients on lower doses with low DMI levels, as is common in the treatment of elderly patients. If comparable dosage is administered, nonlinear increases in DMI levels result in lower OH-DMI/DMI ratios similar to those in younger patients. Although our findings of elevated hydroxy levels in the elderly are consistent with prior reports, the clinical importance of an 11 ng/ml difference, particularly in relation to total drug levels averaging 220 ng/ml, is questioned.

Administration, Oral↗

PubMed1988

Reliability of antidepressant assays: a reference laboratory perspective on antidepressant monitoring.

Chromatography (gas and liquid) and immunoassays are used for monitoring the commonly prescribed tricyclic antidepressants. Many commercially available immunoassays are known to cross react with structurally similar compounds. Chromatographic methods make it possible simultaneously to resolve and quantify amitriptyline, nortriptyline, imipramine, desipramine, trimipramine, doxepin, desmethyldoxepin, protriptyline, and maprotiline-and potentially crossreactive compounds can be separated from the tricyclics. Immunoassays may have a valuable role in initial toxicological screening for the presence of a tricyclic-like compound, and they also may be helpful in a laboratory dedicated to a well-controlled patient group. However, 10% of our specimens contain more or different antidepressants than we are requested to analyze for. With our analysis, we are able to report which antidepressants are present, and in what concentrations. Further, in the case of a potential overdose of tricyclic, the primary purpose for early toxicological analysis to anticipate subsequent clinical complications. Therefore, even in the case of toxicological analysis, it is important to know exactly what tricyclic antidepressant is present rather than just the semiquantitative presence of one or more structurally related compounds, because these various compounds differ markedly in their potential for adverse effects. There are too many potential, and possibly yet unknown, interactions for a reference laboratory routinely to rely on immunoassays for therapeutic drug monitoring or toxicological identification of antidepressants.

Antidepressive Agents, Tricyclic↗