Review of fluoxetine and its clinical applications in premenstrual dysphoric disorder

The largest number of antidepressant treatment trials in premenstrual syndrome and premenstrual dysphoric disorder (PMDD) have been conducted with fluoxetine. Fluoxetine and other selective serotonin re-uptake inhibitors (SSRIs) clearly reduce premenstrual emotional and physical symptoms and improve premenstrual psychosocial functioning. Fluoxetine was the first SSRI to be approved by the FDA as a treatment for the emotional and physical symptoms of PMDD. Fluoxetine 20 mg has been reported to be effective for emotional and physical premenstrual symptoms with continuous daily dosing (every day of the menstrual cycle) and with luteal phase daily dosing (from ovulation to menses). In addition, premenstrual emotional symptoms have been reported to improve with fluoxetine 10 mg in luteal phase daily dosing and with 90 mg 2 and 1 weeks prior to menses. Fluoxetine is generally a well-tolerated treatment for PMDD and discontinuation effects have not been reported with intermittent dosing regimens.     

Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/premenstrual dysphoric disorder?

Current evidence suggests that the accepted treatments for premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) have similar overall efficacy. While these treatments are more effective than placebo, response rates associated with them are far from satisfactory (<60%), such that, irrespective of treatment modality, there remain a significant number of women who are unresponsive to current conventional pharmacological therapy. The available data on response rates of specific types of premenstrual symptoms to, or symptom profiles that are most amenable to, each treatment modality are limited and not well defined because most studies were not designed to assess specific symptom profiles. Those studies that have attempted to evaluate which symptom profiles respond to specific therapies have revealed variations within the individual modalities, as well as between the different modalities. It appears that suppression of ovulation ameliorates a broad range of behavioural as well as physical premenstrual symptoms. SSRIs are most effective for irritability and anxiety symptoms, with lesser efficacy for 'atypical' premenstrual symptoms. GABAergic compounds are most efficacious for anxiety and anxious/depressive symptoms, while dopamine agonists, particularly bromocriptine, are perhaps most efficacious for mastalgia. Overall treatment response rates may improve if treatments are targeted at well-defined subgroups of patients. Re-analysis of available datasets from randomised clinical trials may shed more light on the notion that targeting women with specific premenstrual symptom profiles for specific treatment modalities would improve response rates beyond the current ceiling of approximately 60%. Such information would also improve understanding of the putative pathophysiological mechanisms underlying PMS and PMDD, and may point to a more specific diagnosis of these conditions.     

Hormonal treatments for premenstrual syndrome

Ovarian function appears to play a fundamental role in premenstrual syndrome (PMS). Accordingly, treatment strategies designed to suppress ovulation have generally been found to be effective for treatment of menstrually related syndromes and symptoms. GnRH agonists and Danazol(R) are probably inferior to estrogen, due to their unfavorable side effects profile. In addition, it is worthwhile to emphasize that in spite of the publicity of progesterone treatment for PMS, in most well-controlled studies it has not been shown to be more effective than placebo for the treatment of these syndromes. The efficacy of hormonal treatments that do not suppress ovulation is still controversial.     

Luteal phase administration of agents for the treatment of premenstrual dysphoric disorder

This review focuses on current information about luteal phase administration (i.e. typically for the last 2 weeks of the menstrual cycle) of pharmacological agents for the treatment of premenstrual dysphoric disorder (PMDD). Compared with continuous administration, a luteal phase administration regimen reduces the exposure to medication and lowers the costs of treatment. Based on evidence from randomised clinical trials, SSRIs are the first-line treatment for PMDD at this time. Of these agents, sertraline, fluoxetine and paroxetine (as an extended-release formulation) are approved by the US FDA for luteal phase, as well as continuous, administration. Clinical trials of these agents and citalopram have demonstrated that symptom reduction is similar with both administration regimens. When used to treat PMDD, SSRI doses are consistent with those used for major depressive disorder. The medications are well tolerated; discontinuation symptoms with this intermittent administration regimen have not been reported. Other medications that have been examined in clinical trials for PMDD or severe premenstrual syndrome (PMS) using luteal phase administration include buspirone, alprazolam, tryptophan and progesterone. Buspirone and alprazolam show only modest efficacy in PMS (in some but not all studies), but there may be a lower incidence of sexual adverse effects with these medications than with SSRIs. Symptom reduction with tryptophan was significantly greater than with placebo, but the availability of this medication is strictly limited because of safety concerns. Progesterone has consistently failed to show efficacy for severe PMS/PMDD in large, randomised, placebo-controlled trials.     

Role of bromocriptine and pyridoxine in premenstrual tension syndrome

Premenstrual syndrome (PMS) is a universal problem of women of reproductive age group. No satisfactory treatment is available to treat this syndrome till date. Sixty female patients with PMS in age group of 20-45 years were interviewed. A detailed history and 20 premenstrual symptoms were included for making the diagnosis of PMS. Premenstrual symptom score of each patient was recorded before treatment. Patients were followed up monthly for 3 months after starting treatment, to ascertain the change in score. The patients were divided into 3 groups of 20 patients each - control group, bromocriptine group and pyridoxine group. In control group, patients were kept on ferrous sulphate tablet 100 mg for 3 months, as placebo. There was no significant change in the premenstrual symptoms score at the end of the study period in control group. Bromocriptrine 2.5 mg twice a day and pyridoxine 100 mg/day showed a significant reduction in the mean premenstrual symptom score after 3 months of treatment. It is concluded that both the drugs are effective for treatment of premenstrual syndrome but, pyridoxine showed significantly higher response rate and lesser incidence of side effects than bromocriptine.     

Treatment of premenstrual dysphoric disorder with selective serotonin reuptake inhibitors

Premenstrual dysphoric disorder (PMDD) is considered a severe form of premenstrual syndrome. Symptoms of PMDD occur during the last week of the luteal phase of the menstrual cycle and usually abate at the onset of menses. About 3-8% of all menstruating women experience PMDD, which can lead to significant functional impairment. Several randomized, controlled trials have assessed the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of PMDD. The SSRIs were found to significantly improve symptoms, particularly psychological or behavioral symptoms, during the luteal phase in women with PMDD. Also, SSRIs were found to improve the quality of life in women with PMDD. Headache, fatigue, insomnia, and anxiety were often reported as adverse effects. A decrease in libido or sexual dysfunction also was reported. In recent studies, intermittent SSRI therapy was found to be effective treatment for PMDD and allows a woman to take the drug for only 14 days each month. Intermittent SSRI therapy should be recommended before continuous daily dosing of SSRIs in the treatment of PMDD.     

Recent and future advances in the treatment of PMS, PMD, and menopause

In keeping with the widespread demand for therapy, many different ways of dealing with premenstrual syndrome (PMS), premenstrual dysphoria (PMD) and post menopausal symptoms are presently recommended and practiced. Severe depression associated with PMD is often treated with selective serotonin reuptake inhibitors (SSRI), while milder PMS often receives a number of medical and alternate remedies. Post menopausal symptoms are often avoided by use of hormone replacement therapy (HRT), alternatives for which include natural hormone replacement therapy (nHRT). Alternate therapies and interventions are also practiced widely. The continued need for improved therapies should lead to more extensive consideration of hormone metabolism which is greatly altered by exercise and dietary factors. A full knowledge of the hormone metabolic path from cause to effect is urgently required.     

Evaluation and management of premenstrual syndrome and premenstrual dysphoric disorder

OBJECTIVE: To review premenstrual disorders, their varied symptoms, possible etiology, and treatment options. DATA SOURCES: Published articles identified through MEDLINE (1966-2001) using the search terms premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) and the additional terms treatment and etiology. Additional references were identified from the bibliographies of the retrieved articles. DATA SYNTHESIS: PMS refers to a group of menstrually related disorders that are estimated to affect up to 40% of women of childbearing age. The varied symptoms of PMS include mood swings, tension, anger, irritability, headache, bloating, and increased appetite with food cravings. PMS symptoms occur during the luteal phase of the menstrual cycle and remit with the onset of menstruation or shortly afterward. Approximately 5% of women with PMS suffer from PMDD, a more disabling and severe form of PMS in which mood symptoms predominate. Because no tests can confirm PMS or PMDD, the diagnosis should be made on the basis of a patient-completed daily symptom calendar and the exclusion of other medical disorders. The causes of PMS and PMDD are uncertain, but are likely associated with aberrant responses to normal hormonal fluctuations during the menstrual cycle. For most women, symptoms can be relieved or reduced through lifestyle interventions, such as dietary changes and exercise, and drug therapy with hormonal or psychotropic agents. For PMDD, selective serotonin reuptake inhibitors have recently emerged as first-line therapy. Certain dietary supplements, including calcium, also may be an option for some women. CONCLUSION: PMS and PMDD are complex but highly treatable disorders. Pharmacists can improve the recognition and management of these common conditions by providing patient education on premenstrual symptoms and counseling women on lifestyle interventions and pharmacotherapy to relieve their discomfort.     

Novel therapies for narcolepsy

Narcolepsy is a primary neurological disorder, which often produces disabling symptoms, including excessive daytime sleepiness and cataplexy. Although the precise aetiology of narcolepsy has not been determined, our understanding of the pathophysiology of this complex disorder has grown dramatically during the past several years, especially as it relates to the newly discovered hypocretin system. While symptomatic treatment of narcolepsy is available, the commonly used pharmacological agents are often not completely effective and may be poorly tolerated. The need for new therapeutic tools is, therefore, apparent. This paper explores some exciting new approaches to the treatment of narcolepsy. It is important to emphasise that, although narcolepsy is not a common disorder, new agents for its treatment will undoubtedly find more extensive use in other conditions.     

Drospirenone: a novel progestin

Drospirenone is a novel progestin available in combined oral contraceptives and menopausal hormonal therapy. Similar to its parent compound spirolactone, an analog of spironolactone, drospirenone has antimineralocorticoid and antiandrogenic activity. Combined with ethinyl estradiol in oral contraceptive formulations, drospirenone-containing contraceptives have similar efficacy and safety profiles to other low-dose oral contraceptives, but seem to offer improved tolerability with regard to weight gain, mood changes, acne and treatment of a severe form of premenstrual syndrome called premenstrual dysphoric disorder. Combined with estradiol as a continuous hormone therapy regimen, the compound was shown to reduce vasomotor symptoms, maintain bone mass, have a beneficial effect on body weight and, more importantly, was shown to lower blood pressure in postmenopausal women.     

A clinical guide to antipsychotic drugs.

Antipsychotic medications have altered the treatment of psychosis. The effect of typical agents is presumed to be associated with dopamine D2-receptor blockade. Response to these drugs can be evaluated by measuring target symptoms. Behavioural symptoms are generally first to respond, followed by affective symptoms, and then symptoms of disturbed cognition and perception. Predictors of response include age of onset, premorbid function, family history, cognitive function, ventricle size, and levels of homovanillic acid. As all conventional antipsychotic medications of comparable dose are generally of equivalent efficacy (with the exception of clozapine), choice is based on past response and the patient's tolerance of adverse effects. When antipsychotic agents are administered in the short term to control agitated dangerous behaviour, they can be given intramuscularly and augmented with benzodiazepines. For the ongoing treatment of psychosis, haloperidol 5 mg/day, or its equivalent, is usually sufficient. Continuation of treatment after an acute episode may be decided on the basis of chronicity of the psychotic illness. Relapse rates are higher when patients do not continue to receive medication. Lower maintenance doses may result in higher relapse rates but fewer adverse effects. Long-acting intramuscular depot preparations may be used to aid compliance in long term therapy. Adverse reactions correlate with potency. High potency drugs (i.e. those with greater D2 postsynaptic receptor affinity) are generally associated with extrapyramidal symptoms, including acute dystonic reactions, akathisia, tardive dyskinesia and Parkinsonism. Neuroleptic malignant syndrome is associated with all neuroleptic drugs. Low potency agents may cause orthostatic hypotension, sedation and anticholinergic effects. Clozapine has been shown to be effective in 30 to 40% of patients resistant to previous treatment. It does not cause extrapyramidal symptoms, but does have side effects similar to those of low potency agents and may cause agranulocytosis; it is therefore reserved for those patients who have not responded to therapy with 2 other agents. Several other atypical drugs are currently being investigated.     

Placebo-controlled trial comparing intermittent and continuous paroxetine in premenstrual dysphoric disorder.

Serotonin reuptake inhibitors (SRIs) do not have to be administered continuously to be effective for premenstrual dysphoric disorder (PMDD), but can be given during luteal phases only. This is of practical importance, but also of theoretical interest since it suggests that the onset of action of SRIs is shorter in PMDD than in, for example depression. In this study, both continuous and intermittent SRI administration was compared with placebo, with the special purpose of analyzing if different PMDD symptoms respond differently depending on the treatment regimen. To this end, women meeting slightly modified DSM-IV criteria for PMDD (mean+/-SD age, 37+/-6.3 years) were treated for three menstrual cycles with paroxetine continuously, paroxetine during the luteal phase only, or placebo, the population completing at least one treatment cycle comprising 55-56 subjects per group. Continuous treatment with paroxetine reduced premenstrual symptoms effectively with a response rate of 85%. The effect size was highest for irritability (1.4) and lowest for lack of energy (0.5). Intermittent treatment was as effective as continuous treatment in reducing irritability, affect lability, and mood swings, but had a somewhat weaker effect on depressed mood and somatic symptoms. The study indicates that the response rate when treating PMDD with SRIs is high, and that irritability is a key target symptom. Symptoms such as irritability, affect lability, and mood swings appear to be more inclined to respond rapidly to SRIs, enabling intermittent treatment, than are, for example, the somatic symptoms.     

Atypical antipsychotic drugs in the treatment of Parkinson's disease

Parkinson's disease (PD) patients often develop psychotic symptoms that severely affect quality of life and limit the use of medications to ameliorate motor symptoms. Psychotic symptoms are a major cause for nursing home placement. While these symptoms do not always require treatment, they often do but antipsychotic drugs all share the common pharmacological mechanism of blocking dopamine D2 receptors which may worsen motor problems in this very vulnerable population. Double blind, placebo controlled trials (DBPCT) have shown that clozapine is effective at controlling the psychotic symptoms at doses far below those used in schizophrenia, without worsening motor function, even improving tremor. DBPCT have demonstrated that olanzapine worsens motor function without improving psychosis. Quetiapine has been shown in DBPCT to be free of motor side effects in PD patients but not effective, whereas many open label studies have indicated that quetiapine is effective. The other atypical have been the subjects of conflicting open label reports. The effects of the atypicals in PD psychosis is reviewed.     

Nonsteroidal anti-inflammatory agents in the treatment of primary dysmenorrhea

The physiology of primary dysmenorrhea and its treatment with nonsteroidal anti-inflammatory agents are reviewed. Primary dysmenorrhea involves incapacitating pelvic pain associated with nausea, vomiting, and diarrhea. Currently, it is thought to be caused by an overproduction of prostaglandins that are released as the endometrium degenerates. Since the nonsteroidal anti-inflammatory agents are one class of antiprostaglandin agents, they are frequently prescribed for the relief of dysmenorrhea. Naproxen and naproxen sodium have both been shown to be superior to placebo in subjective and objective assessments of dysmenorrheic patients when administered at the onset of symptoms. Indomethacin studies demonstrate its efficacy over placebo, but the frequency of side effects at the doses used (25-50 mg t.i.d.) diminish its usefulness. Few placebo-controlled studies have been published on ibuprofen, but the studies that have been performed show that ibuprofen is more beneficial than placebo for treating dysmenorrhea with a low incidence of side effects. The fenamates appear to be effective in dysmenorrhea, although they were not studied extensively with placebo and previous experience with mefenamic acid has led to warnings about side effects. Phenylbutazone and oxyphenbutazone have been found to be effective; however, their use has been less frequent since the introduction of the newer less toxic nonsteroidal agents. Comparative studies of the nonsteroidal anti-inflammatory agents have not indicated that one agent is more effective than the others. Until further well-controlled comparative research is performed, any of the agents reviewed would be an appropriate choice in the treatment of primary dysmenorrhea.     

Diagnosis and treatment of premenstrual dysphoric disorder: an update

Premenstrual dysphoric disorder (PMDD) appears in the appendix of the DSM-IV under the heading 'depressive disorder not otherwise specified'. Yet, recently, a group of experts reached a consensus that PMDD is a distinct clinical entity with characteristic symptoms of irritability, anger, internal tension, dysphoria, and mood lability. PMDD is the more severe form of premenstrual symptomatology, whereas premenstrual syndrome (PMS) is milder and more prevalent and both must be differentiated from premenstrual magnification/exacerbation of an underlying major psychiatric disorder or a medical condition. Accurate assessment and diagnosis of significant premenstrual symptomatology is paramount and can be influenced by subjective perception, retrospective versus prospective reporting, and cultural context. The serotonergic system, which is in a close reciprocal relationship with the gonadal hormones, has been identified as the most plausible target for intervention. Results from randomized placebo-controlled trials in women with PMDD have clearly demonstrated that serotonin reuptake inhibitors (SSRIs), with daily or intermittent dosing, have excellent efficacy and minimal adverse effects and should be considered first-line treatment. Luteal phase only SSRI administration may offer an attractive treatment option for a disorder that is itself intermittent. Hormonal interventions, in particular the suppression of ovulation will eliminate premenstrual symptomatology; however, the benefits-risk ratio of these approaches should be carefully evaluated with the patient.     

Treatment decisions,side-effect liability and cost-effectiveness in osteoarthritis

Cost-benefit ratios emphasize benefits as much as they do risks but the consequences of not treating also figure in the equation. For osteoarthritis (OA), most drugs designed to alter the progression have either been found wanting or have been withdrawn. That leaves palliation of symptoms as the search for pharmacological intervention to replace the very effective surgery continues. Guidelines to aid in the search succeed in defining alternatives to amelioration but less satisfactority define disease modifiers. Much of this derives from a misunderstanding: OA is not a disease, though it often provokes symptoms, but rather is the final common pathway of all events at a joint. Treatment can therefore be offered only when OA produces symptoms, and that is too late to reverse the process. If prediction were possible, more effective prophylaxis might be developed. The interferences with life content, life space and life span lead to the therapeutic decisions and their cost-effectiveness. Because symptoms in OA often result from secondary inflammation, anti-inflammatory drugs remain appropriate choices, even though simple analgesics suffice in the short term for pain relief alone. That inflammation may also underlie the inception of the process that leads to OA is self-evident and more effective initial treatment might slow the progression, but the symptoms of established OA are a secondary event, long after the historically elusive primary insult, and warrant careful appraisal of cost-effectivness of interventions as part of risk assessment.     

The use of atypical antipsychotics in the management of schizophrenia

Long-term drug treatment of schizophrenia with conventional antipsychotics has limitations: an estimated quarter to one third of patients are treatment-resistant; conventional antipsychotics have only a modest impact upon negative symptoms (poverty of thought, social withdrawal and loss of affect); and adverse effects, particularly extrapyramidal symptoms (EPS). Newer, so-called atypical, antipsychotics such as olanzapine, risperidone, sertindole and clozapine (an old drug which was re-introduced in 1990) are claimed to address these limitations. Atypical agents are, at a minimum, at least as effective as conventional drugs such as haloperidol. They also cause substantially fewer extrapyramidal symptoms. However, some other adverse effects are more common than with conventional drugs. For example, clozapine carries a significant risk of serious blood disorders, for which special monitoring is mandatory; it also causes troublesome drowsiness and increased salivation more often than conventional agents. Some atypical agents cause more weight gain or QT prolongation than older agents. The choice of therapy is, therefore, not straightforward. At present, atypical agents represent an advance for patients with severe or intolerable EPS. Most published evidence exists to support the use of clozapine, which has also been shown to be effective in schizophrenia refractory to conventional agents. However, the need for compliance with blood count monitoring and its sedative properties make careful patient selection important. The extent of any additional direct benefit offered by atypical agents on negative symptoms is not yet clear. The lack of a depot formulation for atypical drugs may pose a significant practical problem. To date, only two double-blind studies in which atypical agents were compared directly have been published. Neither provides compelling evidence for the choice of one agent over another. Atypical agents are many times more expensive than conventional drugs. Although drug treatment constitutes only a small proportion of the costs of managing schizophrenia, the additional annual cost of the use of atypical agents in, say, a quarter of the likely U.K. schizophrenic population would be about 56 M pound sterling. There is only limited evidence of cost-effectiveness. Atypical antipsychotics are not currently licensed for other conditions where conventional antipsychotics are commonly used, such as behaviour disturbance or dementia in the elderly. Their dose, and place in treatment in such cases have yet to be determined.     

The role of pharmacotherapy in the treatment of patients with borderline personality disorder

Most patients with borderline personality disorder (BPD), especially early in their treatment, will need pharmacotherapy along with supportive or exploratory psychotherapy. A benzodiazepine anxiolytic will suffice for some. Many require more definitive treatment with an antidepressant or a neuroleptic in low dosage. Those with bipolar II comorbidity may benefit from lithium or, if the irritability component is pronounced, from carbamazepine. In practice, a variety of personality factors and comorbid conditions, over-represented in populations of BPD patients, often complicate the clinical picture. Depending upon the mix of these factors, drugs may have to be avoided, nonstandard combinations of drugs may be necessary, or a safer but less effective drug may have to be substituted for a generally more effective drug whose abuse in a suicidal patient might have more dangerous consequences. Examples of complicating factors, namely premenstrual syndrome (PMS), bulimia, agoraphobia, major affective (including bipolar II manic-depressive) disorder, hypersomnia, and so forth are discussed.     

Novel therapies for narcolepsy

Narcolepsy is a primary neurological disorder, which often produces disabling symptoms, including excessive daytime sleepiness and cataplexy. Although the precise aetiology of narcolepsy has not been determined, our understanding of the pathophysiology of this complex disorder has grown dramatically during the past several years, especially as it relates to the newly discovered hypocretin system. While symptomatic treatment of narcolepsy is available, the commonly used pharmacological agents are often not completely effective and may be poorly tolerated. The need for new therapeutic tools is, therefore, apparent. This paper explores some exciting new approaches to the treatment of narcolepsy. It is important to emphasise that, although narcolepsy is not a common disorder, new agents for its treatment will undoubtedly find more extensive use in other conditions.