Evidence-based Resources in Current and Alternative Therapies
Compiled by: Constantine Kaniklidis, medical researcher
[ Depression Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]

Home Depression (Adult)

Bipolar Disorder

  • Bipolar Disorder: General

    Misdiagnosis of bipolar disorder is high (Hirschfeld et al., J Clin Psychiatry (2003): Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder), and clinically accurate early diagnosis is complicated by the fact that patients often present in the depressive phase, which can easily be mistaken for unipolar depression. Bipolar depression, compared with unipolar depression, is more likely to be associated with hypersomnia, motor retardation, mood lability, early onset, and a family history of bipolar disorder.

    Furthermore, most therapy appropriate for unipolar depression using traditional antidepressants can increase the risk of manic switch or cycle acceleration in bipolar disorder, especially in those with a family history of bipolarity and suicide: see Bowden (Expert Opin Investig Drugs (2001): Novel treatments for bipolar disorder), Bowden (J Affect Disord (2005): A different depression: clinical distinctions between bipolar and unipolar depression), and McIntyre et al. (Can Fam Physician (2004): Treating Bipolar Disorder). In addition, most currently available mood stabilizers, though effective in managing mania, do not effectively resolve depression.

    The paper of N. Kaye (J Am Board Fam Pract (2005): Is Your Depressed Patient Bipolar?) has invaluably clarified the key errors in clinical practice involved in misdiagnosing bipolar depression as unipolar depression, providing critical clinical guidance as to how to distinguish between the two entities. In short Kaye notes that bipolar disorders can be seen as exhibiting three distinct phases: the depressed phase, which mimics the clinical picture of major depression (lower pole), the manic or hypomanic phase (upper pole), and euthymia, or the asymptomatic phase. Manic and hypomanic episodes are characterized by grandiosity, inflated self-esteem, diminished need for sleep, increased goal-directed activity, and talkativeness. Then mania and hypomania are themselves distinguished by the fact that mania is typically of longer duration, causes more functional impairment, and may be associated with psychotic features (patients sometimes present with mixed episodes, in which patients experience both manic and depressive symptoms, with associated severe functional impairment).

    Under current DSM-IV-TR criteria, only one lifetime manic or mixed episode is required for a diagnosis of bipolar I disorder; while the manual specifies that at least one hypomanic and one depressive episode occur in the absence of manic or mixed episodes for a diagnosis of bipolar II disorder.



    Diagnosing Bipolar Disorder
    In addition, the one-page five-minute MDQ (Mood Disorder Questionnaire), developed by Dr. Robert M.A. Hirschfeld (Hirschfeld et al., Am J Psychiatry (2000): Development and Validation of a Screening Instrument for Bipolar Spectrum Disorder: The Mood Disorder Questionnaire), is a brief standardized screening instrument consisting of 13 yes/no queries + two questions concerning the function and timing of symptoms; a validation study found that an MDQ screening score of 7 or more items yields good sensitivity (at 73%) and very good specificity (at 90%). Isometsä et al. (BMC Psychiatry (2003): The Mood Disorder Questionnaire improves recognition of bipolar disorder in psychiatric care) found the MDQ to be a feasible screen for bipolar disorder. See also Das et al. (JAMA (2005): Screening for Bipolar Disorder in a Primary Care Practice) and Hirschfeld (J. Am. Board Fam. Pract (2005): Screening for Bipolar Disorder in Patients Treated for Depression in a Family Medicine Clinic). The MDQ is available online from numerous sources (see for example: BipolarHelpCenter: Mood Disorder Questionnaire; also downloadable as pdf: MDQ PDF).

  • Forms of Bipolar Disorder
    Three distinct major forms of bipolar disorder are currently recognized, summarized below. See Morehead Well-Connected Report (2004): Bipolar Disorder; Bipolar Disorder Today: Bipolar Disorder DSM IV Criteria); Bowden (MedGenMed (2002): Diagnosis of Bipolar Disorders: Focus on Bipolar Disorder I and Bipolar Disorder II); The Merck Manual of Diagnosis and Therapy: Bipolar Disorder; and DBSA: Bipolar Disorder for accessible discussions of these classifications.



    Bipolar I Disorder
    This is characterized by one or more manic episodes or mixed episodes (symptoms of both a mania and a depression occurring nearly every day for at least 1 week) and one or more major depressive episodes. Bipolar I disorder represents the most severe form of the illness marked by extreme manic episodes.



    Bipolar II Disorder
    This is characterized by one or more depressive episodes accompanied by at least one hypomanic episode. Hypomanic episodes have symptoms similar to manic episodes but are less severe, but must be clearly different from a person’s non-depressed mood. For some, hypomanic episodes are not severe enough to cause notable problems in social activities or work. However, for others, they can be both troublesome and disruptive. Bipolar II disorder may be misdiagnosed as depression he signs of hypomania are missed. In a recent DBSA (Depression and Bipolar Support Alliance) survey, nearly seven out of ten people with bipolar disorder had been misdiagnosed at least once. Sixty percent of those people had been diagnosed with depression.



    Cyclothymic Disorder
    This disorder is characterized by chronic fluctuating moods involving periods of hypomania and depression. The periods of both depressive and hypomanic symptoms are shorter, less severe, and do not occur with regularity as experienced with bipolar II or I. However, these mood swings can impair social interactions and work. Many, but not all, people with cyclothymia develop a more severe form of bipolar illness.



    Agitated Depression
    Although not an official classification, Maj et al. (Am J Psychiatry (2003): Agitated Depression in Bipolar I Disorder: Prevalence, Phenomenology, and Outcome) have sought to delineate another potential category or subcategory of bipolar disorder, which they refer to as agitated depression in Bipolar I Disorder: as they note, patients with agitated depression were consistently not elated or grandiose, but one-fourth had the cluster of symptoms with racing thoughts, pressured speech, and increased motor activity, and one-fourth had the paranoia-aggression-irritability cluster; see also the commentary of Sato et al. (Am J Psychiatry (2003): Evidence of Depressive Mixed States).

  • Lamotrigine
    Lamotrigine has shown activity in bipolar depression and has a very low risk of manic switch. Lamotrigine has demonstrated efficacy in both acute bipolar depression and maintenance efficacy in rapid cycling bipolar patients, especially those patients with bipolar II disorder (principally manifested as depression). Two placebo-controlled trials demonstrated the efficacy of lamotrigine in acute bipolar depression. Calabrese et al. (J Clin Psychiatry (1999): A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression) found lamotrigine, 50 mg/day and 200 mg/day, significantly more efficacious than placebo in reduction of depressive symptoms in patients with bipolar I depression in a 7-week trial, with a trend for greater efficacy of 200 mg/day over 50 mg/day, There were no significant differences in switch rates between the treatment groups. Frye et al. (J Clin Psychopharmacol (2000): A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders) compared lamotrigine, gabapentin, and placebo in a crossover study in patients with treatment-refractory rapid-cycling bipolar I and II disorders. Among the 3 treatment groups, only lamotrigine was associated with significant reductions in depressive symptoms.

    More recently, Goodwin et al. (J Clin Psychiatry (2004): A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder) analyzed two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients, confirming the earlier findings that lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania. And Manning et al. (J Affect Disord (2005): Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament) found that lamotrigine induced prolonged illness remissions in a substantial number of female patients whose symptoms were both complex and refractory, most of whom manifested cyclothymic and depressive temperaments, and were refractory to multiple antidepressant and antidepressant/mood stabilizer combinations, before remitting with lamotrigine augmentation or monotherapy.

  • Other Monotherapy:
    As demonstrated by Bauer & Mitchner (Am J Psychiatry (2004): What Is a "Mood Stabilizer"? An Evidence-Based Response) lithium, valproate, and olanzapine had unequivocal evidence for efficacy in acute manic episodes, lithium in acute depressive episodes and in prophylaxis of mania and depression, and lamotrigine in prophylaxis (relapse polarity unspecified).

    Furthermore, Gijsman et al. (Am J Psychiatry (2004): Antidepressants for Bipolar Depression: A Systematic Review of Randomized, Controlled Trials) reviewed the literature and found, against the widespread concerns of antidepressant-induced switching, that antidepressants are effective in the short-term treatment of bipolar depression and that the trial data do not suggest that switching is a common early complication of such treatment.

  • Older Anticonvulsants
    Although early anticonvulsants divalproex and carbamazepine are still prescribed for bipolar disorders, side effects profiles are limiting (see Goldberg & Citrome, Postgrad Med (2005): Latest therapies for bipolar disorder. Looking beyond lithium): with divalproex, these may be nausea, sedation, weight gain, alopecia, and thrombocytopenia, necessitating frequent liver function monitoring, while with carbamazepine, the main concern is induction of metabolism of that agent and of many other agents, necessitating dose adjustments for all affected medications, with adverse effects including sedation and a small risk of liver toxicity and agranulocytosis (the keto analogue of carbamazepine, oxcarbazepine, has shown possible pharmacodynamic efficacy in bipolar disorder, but RCT evidence for efficacy is not to date available).



  • Second-generation Antipsychotics
    Currently, five second-generation antipsychotics have received FDA approval for monotherapy in acute bipolar mania: olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify), with olanzapine, risperidone, quetiapine also approved indications for add-on therapy, and olanzapine in addition approval for maintenance therapy. These atypical agents (olanzapine, risperidone and quetiapine) have demonstrated efficacy against the manic phase of bipolar disorder and appear also to have potential in the depressive phase. Quetiapine appears to also be efficacious as monotherapy in acute bipolar depression (Calabrese et al., Am J Psychiatry (2005): A Randomized, Double-Blind, Placebo-Controlled Trial of Quetiapine in the Treatment of Bipolar I or II Depression), including suicidal thoughts, anxiety, sleep quality and global quality of life (Keck, Bipolar Disord (2005): Bipolar depression: a new role for atypical antipsychotics?). In the review of Post & Calabrese (Expert Rev Neurother (2004): Bipolar depression: the role of atypical antipsychotics), olanzapine monotherapy significantly improved depressive symptoms compared with placebo in an 8-week RCT clinical study, but the magnitude of the clinical effect was small, although the observed improvement in depressive symptoms became moderately large when olanzapine was combined with fluoxetine (Prozac). in another 8-week RCT clinical study, quetiapine monotherapy also resulted in significant improvements compared with placebo in patients with either bipolar I or II disorder, but in this case the effect size was large. Finally, a 6-month open-label study of risperidone added to ongoing therapy demonstrated improvements in depressive symptoms in patients with bipolar and schizoaffective disorders experiencing a manic, hypomanic, mixed or depressive episode.

    Gao & Calabrese (Bipolar Disord (2005):     Newer treatment studies for bipolar depression) found that lamotrigine only significantly reduced core symptoms of depression compared with placebo, and that olanzapine, olanzapine–fluoxetine combination (OFC), and quetiapine are effective in the acute treatment of bipolar depression, and lamotrigine is more effective in preventing bipolar depression compared with lithium and divalproex.
    In addition, GAO and Calabrese (above) found both pramipexole (Mirapex), a dopamine D2/D3 receptor agonist, and omega-3 fatty acids augmentation to a mood stabilizer had superiority to placebo in reducing depressive symptoms (on the efficacy of pramipexole as an antidepressant in bipolar disorder, see also Goldberg et al., Am J Psychiatry (2004): Preliminary Randomized, Double-Blind, Placebo-Controlled Trial of Pramipexole Added to Mood Stabilizers for Treatment-Resistant Bipolar Depression). They found topiramate (Topamax) augmentation of an mood stabilizer was equally as effective as bupropion-SR.

    GAO& Calabrese (above) further found that patients treated with a mood stabilizer responded well to the addition of agomelatine (Valdoxan), a melatonin receptor agonist with 5-HT2C antagonist properties. However, the study found that inositol and repetitive transcranial magnetic stimulation were not superior to placebo. Finally, lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to placebo in preventing depressive relapses. All agents were relatively well tolerated.

    Evidencewatch Warning:
    Anticonvulsants and Cognitive Impairment
    However Evidencewatch notes that that cognitive impairment may be a concern with both topiramate and lamotrigine. In their review of the cognitive effects of anticonvulsant drugs, Aldenkamp et al. (Epilepsia (2003): Newer Antiepileptic Drugs and Cognitive Issues) concluded that clear clinical evidence for topiramate-induced cognitive impairment, especially for verbal memory parameters such as verbal IQ, verbal fluency, and verbal learning, with some somnolence, psychomotor slowing, speech disorders, and concentration and memory difficulties for escalating the topiramate dose to 200 or 400 mg/day. Kockelmann et al. (Epilepsy Behav (2004): Cognitive profile of topiramate as compared with lamotrigine in epilepsy patients on antiepileptic drug polytherapy: relationships to blood serum levels and comedication) also found that patients on topiramate exhibit a cognitive pattern with specific impairment in executive functions (phonematic verbal fluency, memory spans, and working memory). This contrasts sharply with monotherapy and adjunctive therapy with lamotrigine which was associated with improved cognitive functioning and reduced neurocognitive side effects (see Aldenkamp et al., Epilepsy Behav (2001): A Systematic Review of the Effects of Lamotrigine on Cognitive Function and Quality of Life); also Ginsberg et al. J Clin Psychiatry (2004): Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder),



    Olanzapine-Fluoxetine
    In 2003, Symbyax, a combination of olanzapine and the SSRI antidepressant fluoxetine, became the first combination therapy approved by the FDA for treatment of acute bipolar depression. Tohen et al. (Arch Gen Psychiatry (2003): Efficacy of Olanzapine and Olanzapine-Fluoxetine Combination in the Treatment of Bipolar I Depression) found combined olanzapine-fluoxetine to be more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.



    Efficacy of Second-generation Antipsychotics
    Evidence of efficacy has been sufficiently demonstrated across numerous well-controlled studies that the American Psychiatric Association advises the integration of second-generation antipsychotics with lithium or certain anticonvulsant medications at the outset of therapy for severe forms of acute mania, and further advises ongoing use of second-generation antipsychotics as required to prevent recurrence (Amer Psychiatric Assoc: Practice Guideline for the Treatment of of Patients with Bipolar Disorder (Second Edition)). Illness subtypes for which second-generation antipsychotics may have distinct value, including (1) prior lack of response to lithium or anticonvulsant drugs, (2) mixed mania, (3) rapid cycling, (4) substance abuse or other psychiatric comorbidities, (5) bipolar depression, and (6) psychotic manias.

    The available evidence suggests both short- and long-term comparabilities in efficacy of the various antipsychotics in bipolar disorder, although olanzapine may be superior to lithium for mania relapse prevention).



    Adverse Events:
    Second-Generation Antipsychotics
    With respect to adverse events, the FDA requires a warning about hyperglycemia and diabetes in the product labeling of these second-generation antipsychotics, with more concern associated with olanzapine, quetiapine, and risperidone (Risperdal) than for ziprasidone or aripiprazole. Warnings about tardive dyskinesia and neuroleptic malignant syndrome remain; however, the risk of these events is substantially less than for first-generation antipsychotics and is likely related to a much lower propensity for second-generation antipsychotics to cause extrapyramidal symptoms.

    Evidencewatch Commentary:
    However, despite the FDA-required warning concerning the association of antipsychotic agents and diabetes, Bushe & Leonard in their recent critical review (Br J Psychiatry Suppl (2004): Association between atypical antipsychotic agents and type 2 diabetes: review of prospective clinical data) of diabetogenic risk between antipsychotic medications this issue noted that the claimed association is largely based on retrospective studies not controlled for important confounders; their review found (1) no difference in the incidence of glycemic abnormalities between placebo cohorts and antipsychotic medication cohorts; (2) no significant difference between any of the antipsychotic medications studied in terms of their association with glycemic abnormalities; and that (3) treatment-related weight gain did not appear to increase the risk of developing diabetes.

    Adverse Events:
    Antidepressants for Bipolar Depression
    There are numerous cautions in the literature against the induction of (hypo)mania consequent to the use of antidepressants in bipolar disorder. However, the recent critical review of Visser (World J Biol Psychiatry (2005): Bipolar disorder, antidepressants and induction of hypomania or mania. A systematic review) found no strong evidence that use of antidepressants in bipolar disorder increases the risk of (hypo)mania.



  • Combination Therapy:
    Given that bipolar disorder patients frequently don't respond sufficiently to treatment with a single mood stabilizer, psychiatrists frequently employ combination therapy and add
    (1) antipsychotics,
    (2) antiepileptics, or
    (3) antidepressants
    to mood stabilizers. Evidence suggests that such combination therapy can be more effective than monotherapy in controlling breakthrough or treatment-resistant episodes.

    Thus, atypical antipsychotics have been shown to be effective adjunctive treatments for mania and for patients with psychotic symptoms during a depressive episode, while the combination of a mood stabilizer and the antiepileptic lamotrigine or an antidepressant has been found to control bipolar depression, with lamotrigine therapy being especially useful as maintenance treatment of bipolar I disorder; see Bowden (J Clin Psychiatry (2004: Making optimal use of combination pharmacotherapy in bipolar disorder) who notes in this connection that the APA (American Psychiatric Association) guideline for the treatment of bipolar disorder recommends optimizing individual medications before switching to combination therapy. The clinical challenge is selecting a combination treatment regimen with an acceptable side effect profile given the propensity for patients to discontinue therapy they cannot tolerate. Careful and continued monitoring of adverse effects is critical.

    In addition, also FDA-approved for the treatment of depression and depressive episodes in bipolar disorder is a combination of olanzapine and fluoxetine. And as noted by Bowden (J Clin Psychiatry (2005): Treatment Options for Bipolar Depression) psychoeducation has also been examined as a possible treatment for depression in bipolar disorder, and a study has shown that patients receiving psychoeducation plus medication may have a lower rate of relapse than patients who receive medication alone.

    Other effective combination regimens for which RCT studies provide good evidence (Bowden (Expert Opin Investig Drugs (2001): Novel treatments for bipolar disorder) are risperidone or olanzapine in combination with lithium or valproate; these yield greater improvement in acute mania than the mood stabilizers alone. Similarly, valproate combined with antipsychotics provided greater improvement in mania than antipsychotic medication alone and resulted in lower dosage of the antipsychotic medication; see also Medscape (2004): Stabilizing Depression in Bipolar Disorder), especially the contributions of Herman: Lamotrigine: A Depression Mood Stabilizer and Calabrese: Depression Mood Stabilization: Novel Concepts and Clinical Management.

  • Maintenance Therapies
    Muzina and Calabrese (Aust N Z J Psychiatry (2005): Maintenance therapies in bipolar disorder: focus on randomized controlled trials) have completed a systematic review of RCTs on bipolar disorder :maintenance therapies, finding that:

    (1) Lithium is a highly effective prophylactic antimanic agent and remains the gold standard for overall preventative efficacy in bipolar disorder, especially in decreasing manic and hypomanic relapses, while possessing possess the greatest antidepressant effect. Cipriani et al (Am J Psychiatry (2005): Lithium in the Prevention of Suicidal Behavior and All-Cause Mortality in Patients With Mood Disorders: A Systematic Review of Randomized Trials) found lithium to be effective in the prevention of suicide, deliberate self-harm, and death from all causes in patients with mood disorders (in bipolar disorder and unipolar depression, schizoaffective disorder, dysthymia, and rapid cycling).

    And in seeking to resolve discrepancies in lithium studies, Severus et al. (J Clin Psychopharmacol (2005): Is the prophylactic antidepressant efficacy of lithium in bipolar I disorder dependent on study design and lithium level?) have found that lithium's efficacy against manic relapse/recurrence is robust at plasma levels between 0.8 and 1.2 mmol/L, whereas lithium's efficacy against depressive relapse/recurrence may be more modest and dependent on whether a response during the preceding acute episode was achieved by lithium treatment, and that furthermore, it might be advisable to continue lithium without interruption at the same dose/plasma level, which yielded the initial response; they observe that a lithium level between 0.5 and 0.8 mmol/L may be equally efficacious against overall relapse and associated with equal or even superior efficacy regarding depressive relapse/recurrence.

    However, Deshauer et al. (Bipolar Disord (2005): Re-evaluation of randomized control trials of lithium monotherapy: a cohort effect) have quantified the impact of pre-randomization enrichment designs and diagnostic drift on randomized controlled trials (RCTs) of lithium maintenance therapy, and given that lithium maintenance RCTs differ in patient selection, design, and outcome, suggesting a potential cohort effect associated with the use of pre-randomization enrichment phases and, to a lesser extent, with diagnostic drift.

    Adverse Effects: Lithium has numerous side effects, a narrow therapeutic index, and carries the risk of fatal overdose (see PDRhealth: Eskalith (Lithium Carbonate)).

    (2) The anticonvulsant Divalproex (Depakote) may also prevent recurrent bipolar mood episodes (see, among others, the randomized, double-blind, parallel-group, multicenter study of Gyulai et al, Neuropsychopharmacology (2004): Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression who found that divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder), but there is nonetheless only a relative small number of controlled maintenance studies to make this conclusion more definitive.
    Adverse Effects: Divalproex is associated with weight gain, tremor, hepatotoxicity, and many drug-drug interactions (see PDRhealth: Depakote (Divalproex (Valproic Acid)).

    (3) Extensive and well-designed research supports the use of lamotrigine (Lamictal), another anticonvulsant, in the acute and prophylactic management of bipolar I disorder. It also offers a spectrum of clinical effectiveness complementing lithium: it appears to stabilize mood 'from below baseline' by preventing episodes of depression, and is also effective in rapid-cycling bipolar II disorder.
    Adverse Effects: Although lamotrigine must be carefully titrated and monitored to avoid the possibility of serious rash, it does not require blood monitoring and is associated with minimal weight gain, sexual side effects, sedation, or cognitive impairment (see PDRhealth: Lamictal (Lamotrigine)).

    (4) Carbamazepine (Tegretol), still another anticonvulsant, may be a useful alternative to lithium, divalproex and lamotrigine, especially for patients with a history of mood-incongruent delusions and other comorbidities, but the controlled evidence is more equivocal for this agent's efficacy, and it appears it may lose some of its prophylactic effect over time.
    Adverse Effects: Carbamazepine, which is actually not FDA-approved for the treatment of bipolar disorders, has nonetheless been demonstrated in rigorous studies to be efficacious, but it requires serum level monitoring and carries a risk of hyponatremia and a low risk of blood dyscrasia (see PDRhealth: Tegretol (Carbamazepine)).

    (5) Finally, emerging data continue to support the growing use of atypical antipsychotics, particularly olanzapine (Zyprexa), as a maintenance therapy for bipolar disorder.
    Adverse Effects: Olanzapine, like other atypical antipsychotics, have been associated with a dysmetabolic syndrome marked by weight gain, increased risk of diabetes, and elevated triglycerides, occasionally accompanied by pancreatitis. Therefore, monitoring of patients is
    required when these agents are to be used in the
    longer term, in conjunction with the Consensus Statement on Antipsychotic Medications and Obesity (ADA/APA/AACE/NAASO (American Diabetes Association/American Psychiatric Association/ American Association of Clinical Endocrinologists; North American Association for the Study of Obesity; published in Diabetes Care (2004): Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes); and see the response by E. Barrett to various criticisms and comments on the Consensus Statement (E. Barrett, Diabetes Care (2004): Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes
    Response to Holt, Citrome and Volevka, Isaac and Isaac, and Boehm et al.    ). See also Henderson et al. (Arch Gen Psychiatry (2005): Glucose Metabolism in Patients With Schizophrenia Treated With Atypical Antipsychotic Agents: A Frequently Sampled Intravenous Glucose Tolerance Test and Minimal Model Analysis) who found that both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects; and J. Rosack (Psychiatric News (2004): Antipsychotics’ Diabetes Risk Prompts Call for Better Assessment).

    However, against this Morris and Mohammed (J Psychopharmacol (2005): Metabolism, lifestyle and bipolar affective disorder) reviewed whether the risk of obesity and related morbidity and mortality are raised in bipolar disorder, arguing that reduced exercise and poor diet, frequent depressive episodes comorbidity with substance misuse and poor quality general medical care contribute to the additional risk of these medical problems in people with bipolar depression. They conclude that there is insufficient evidence of an association of any any of these factors with specific drug treatments or that patients with bipolar disorder are intrinsically more sensitive than other patients to weight gain and medical problems associated with long-term use of psychotropic medication, and that in fact long-term treatment of bipolar disorder with lithium, antipsychotics and tricyclic antidepressants may reduce overall mortality.


Major Depressive Disorder (MDD)

  • Types of Depression:
    [MDD = major depressive disorder]
    MDD (major depressive disorder) or unipolar depression -     characterized by depressed mood, hopelessness, helplessness, intense feelings of guilt, sadness, low self esteem, thoughts of self harm, and suicide - is an important factor in disability worldwide, with up to 15% of MDD patients eventually committing suicide (Davies et al., BMJ (2001): Depression, suicide, and the national service framework).

    Within MDD (major depressive disorder), it is common to differentiate entities of recurrent depression, treatment-resistant depression, chronic depression, atypical depression, and
    • psychotic depression. Depression may present with atypical features, the most common being overeating and oversleeping. The syndrome is also associated with mood reactivity and a
    long-standing pattern of interpersonal rejection and over-sensitivity. Coexisting diagnoses of panic disorder, substance abuse and somatisation disorder may
    also be common.

  • Traditional Antidepressant Drugs:
    - TCAs (tricyclic antidepressants)
    - SSRIs (selective serotonin reuptake inhibitors)
    - MAOIs (monoamine oxidase inhibitors)
    - Third Generation Antidepressants
       including dual mechanism SNRIs
       (Serotonin and Noradrenaline Reuptake Inhibitors)

  • TCAs:
    TCAs (amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), dothiepin hydrochloride (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Gamanil, Lomont), nortriptyline (Pamelor), protriptyline (Vivactil), trimipramine (Surmontil)) have equal efficacy compared with alternative antidepressants but are less well tolerated, particularly in outpatients. With respect to inpatients, there is evidence suggesting that there is a statistically significant difference favoring TCAs over alternative antidepressants on reducing depression symptoms by the end of treatment, but the size of this difference is unlikely to be of clinical significance. However, there is strong evidence suggesting that there is a clinically significant difference favoring alternative antidepressants over TCAs on reducing the likelihood of leaving treatment early due to side effects.

    Recently, Arroll et al. (Ann Fam Med (2005): Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis) noted the absence of systematic reviews of depression treatment comparing antidepressants with placebo, disallowing concluding efficacy in primary care; their systematic review is the first comparing antidepressants with placebo for treatment of depression in a primary care setting. They found that both TCAs and SSRIs are effective, and were the first to show that even low-dose TCAs (100 mg or 75 mg) are effective in primary care.



  • MAOIs:
    Monoamine oxidase inhibitors (MAOIs) (Isocarboxazid (Marplan), Moclobemide (Aurorix, Manerix, Moclodura),
    Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Selegiline, Eldepryl)) exert their therapeutic effect by binding irreversibly to monoamine oxidase, the enzyme responsible for the degeneration of monoamine neurotransmitters such as noradrenaline and serotonin. This results in increased monoamine neurotransmission.

    All MAOIs have the potential to induce hypertensive crisis if foods containing tyramine (also metabolized by MAO) are consumed or drugs that increase monoamine neurotransmission are co-prescribed, so that such foods and drugs must be avoided for at least 14 days after discontinuing MAOIs.

    In sum, such dietary restrictions, coupled with potentially serious drug interactions, and the availability of safer classes of antidepressants have led to these irreversible MAOIs being infrequently prescribed. Nonetheless, MAOIs are still widely cited as being the most effective antidepressants for the treatment of atypical depression for achieving remission and response, although the latest evidence suggests this to be true largely in a clinical advantage of one MAOI agent, phenelzine, over TCAs; thus it is relevant to note the findings of NICE (2004): Depression: Management of Depression in Primary and Secondary Care [National Clinical Practice Guideline Number 23 (15 Dec 2004)] and the MHRA (2005): Safety of Selective Serotonin Reuptake Inhibitor Antidepressants [Letter to Healthcare Professionals (18 Feb 2005)] that compared with SSRIs (especially fluoxetine), there is evidence of no difference on mean endpoint scores, and insufficient evidence on other outcome measures    .

  • SSRIs

     The Major SSRIs
    Citalopram (Celexa)
    Escitalopram (Lexapro)
    Fluoxetine (Prozac, Sarafem)
    Fluvoxamine (Luvox)
    Paroxetine (Paxil, Paxil CR)
    Sertraline (Zoloft)

    The selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin into the presynaptic neurone thus increasing neurotransmission. Although they ‘selectively’ inhibit serotonin reuptake, they are not serotonin specific: some of the drugs in this class also inhibit the reuptake of noradrenaline and/or dopamine to a lesser extent.

    As a class, they are associated with fewer anticholinergic side effects and are less likely to cause postural hypotension or sedation. Dosage titration is not routinely required so subtherapeutic doses are less likely to be prescribed.

    They are also less cardiotoxic and much safer in overdose than TCAs or MAOIs. Tata et al. (Heart (2005): General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction) concluded that although antidepressant prescriptions are associated with an increased risk of MI, (1) the size of these effects is similar for TCA and SSRI exposures, and (2) that nonetheless, the lack of specificity between types of antidepressants and the lower risks found in the self controlled analysis suggest that these associations are more likely due to factors relating to underlying depression and health services utilization than to specific adverse drug effects. Given these advantages, SSRIs are in widespread use as better tolerated first-line antidepressants.

    The most problematic side effects of this class of drugs are nausea, diarrhea and headache. Fluvoxamine, fluoxetine and paroxetine are potent inhibitors
    of various hepatic cytochrome metabolizing enzymes
    precipitating many significant drug interactions. Sertraline is less problematic in this connection, although enzyme inhibition is dose-related, with citalopram being relatively safe in this regard. All told, the SSRI group has the advantage of ease of dosing and low toxicity in overdose, with better tolerability than TCAs. SSRIs are also safer than TCAs in overdose.

    Common adverse effects include GI upset (nausea and diarrhea), central nervous system effects (dizziness, agitation, insomnia, and tremor), male and female sexual dysfunction (erectile, desire, orgasm, ejaculation, satisfaction, vaginal lubrication), and changes in energy level (i.e., fatigue, restlessness). Extrapyramidal symptoms are relatively rare and seem to be most common with paroxetine. [For more information on SSRI-induced sexual dysfunction, see our discussion Antidepressants and SD (sidebar).]

    SSRIs may also increase the risk of upper gastrointestinal bleeding, probably by altering platelet function. This risk seems to be increased in people who are also taking low-dosage aspirin or nonsteroidal anti-inflammatory drugs, who have a history of gastrointestinal bleeding, or who are elderly (van Walraven et al., BMJ (2001): Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study); Meijet et al., Arch Intern Med (2004): Association of Risk of Abnormal Bleeding With Degree of Serotonin Reuptake Inhibition by Antidepressants ). Unpublished and reported findings have also raised concern about the potential for an increase in incidence gastrointestinal bleeding and bleeding from other sites (P. Padhan, Annlas Online (2005): Newer Antidepressants and Risk of Bleeding).

    Although overall there is little compelling evidence to suggest an efficacy advantage of any one SSRI over another.

    For escitalopram (Lexapro) - the most serotonin selective SSRI and a racemic mixture of two forms of citalopram (Celexa), the s-citalopram and r-citalopram - there is evidence suggesting that there is a statistically significant difference favoring escitalopram over other antidepressants on (1) increasing the likelihood of patients achieving a 50% reduction in depression symptoms, (2) reducing depression symptoms, although the size of these differences is unlikely to be of clinical significance. However, there is evidence to suggest that there is no clinically significant difference between escitalopram and other antidepressants on increasing the likelihood of patients achieving remission (NICE and MHRA studies, cited above). Nonetheless, differences in the clinical profiles of these agents may be leveraged in choosing the optimal therapy for individual patients or classes of patients (see Anderson & Edwards, Advances in Psychiatric Treatment (2001): Guidelines for Choice of Selective Serotonin Reuptake Inhibitor in Depressive Illness; see especially their tables Distinguishing features of individual selective serotonin reuptake inhibitors (SSRIs) , and Guidelines for choosing an individual selective serotonin reuptake inhibitor (SSRI)).

    These findings are in essential agreement with those of Hansen et al. (Ann Intern Med (2005): Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder) who also concluded that overall, second-generation antidepressants probably do not differ substantially for treatment of major depressive disorder, and that therefore the choice of an agent that is most appropriate for a given patient is a clinically difficult problem. Meta-analyses did show a modest but statistically significant additional treatment effect for sertraline (Zoloft) and venlafaxine (Effexor) compared with fluoxetine (Prozac, Sarafem). These researchers noted the methodological problems: (1) fully about 96% of comparative trials were sponsored by or had at least 1 author affiliated with a pharmaceutical company, with the remaining trials not reporting funding sources, thus raising the potential for publication bias; (2) adverse event profiles differed among drugs, but the degree and quality of adverse event assessment varied, and only 13% of trials used a standardized scale to assess adverse events.

    In sum, SSRIs are relatively well-tolerated drugs with efficacy comparable to alternative antidepressants, and may be particularly suitable for (1) women who may respond preferentially to SSRIs and (2) for those with suicidal intent, due to their safety in overdose.

  • SSRIs and OCD
    SSRIs are well established in the treatment of obsessive-compulsive disorder (OCD), both in its adult and pediatric forms (Grist et al, CNS Spectr (2003): WCA recommendations for the long-term treatment of obsessive-compulsive disorder in adults). The pharmacological treatment of OCD includes the tricyclic antidepressant clomipramine and the SSRIs, and although all SSRIs have shown benefit in acute treatment trials, fluvoxamine, fluoxetine, and sertraline have also demonstrated benefit in long-term treatment trials of at least 24 weeks (note: only clomipramine, sertraline, and fluvoxamine are FDA-approved for use in children and adolescents). Treatment guidelines recommend first-line use of an SSRI over clomipramine, given clomipramine's less favorable adverse-event profile, with pharmacotherapy being sustained for a minimum of 1-2 years before considering very gradual withdrawal.

    In addition, some third generation so-called dual mechanism drugs such as mirtazapine (Koran et al. J Clin Psychiatry (2005): Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation) appear to also be of benefit in OCD treatment; mirtazapine can also be used as part of an augmentation strategy in OCD therapy: Pallanti et al. (J Clin Psychiatry (2004): Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: a pilot study) found earlier onset of response action in OCD symptoms and reduced undesired side effects when mirtazapine was added to citalopram. And March et al. (J Child Adolesc Psychopharmacol (2006): Treatment Benefit and the Risk of Suicidality in Multicenter, Randomized, Controlled Trials of Sertraline in Children and Adolescents) reviewed the balance between the benefits of treatment and the risk of suicidality in children and adolescents in multicenter, randomized, controlled trials of sertraline (Zoloft) versus placebo, finding a positive benefit-to-risk ratio for sertraline in adolescents with MDD and in patients of all ages with OCD.

    Finally, as noted by S. Aronson (eMedicine (2004) : Obsessive-Compulsive Disorder) the dual mechanism agents venlafaxine (Effexor) and duloxetine (Cymbalta) hypothetically also have efficacy in OCD, with safety and tolerability profiles comparable to those of the SSRIs, although neither is currently FDA-approved specifically for OCD treatment.



    Bupropion (Wellbutrin, Zyban)
    Bupropion is a weak reuptake inhibitor for norepinephrine
    and dopamine. Although originally launched as an antidepressant, it has been recently redirected as an aid for smoking cessation and obesity control. In addition, it appears that it can be used in the prevention of the onset of autumn-winter depression: it's possible to prevent recurrence of seasonal major depressive episodes by beginning bupropion treatment early in the season before the onset of SAD (Seasonal affective disorder) symptomology (Modell et al., Biol Psychiatry (2005): Seasonal Affective Disorder and Its Prevention by Anticipatory Treatment with Bupropion XL).

    The balance of the evidence suggests that bupropion and the SSRIs are equivalently effective in the treatment of depression, with sexual dysfunction commonly presenting as a complication of SSRI therapy, whereas treatment with bupropion induced no more sexual dysfunction than placebo (Thase et al., Clin Psychiatry (2005): Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials). Furthermore, bupropion is less likely than other antidepressants to cause weight gain and sexual dysfunction, known to be the two side effects that are of greatest concern to patients and with the greatest impact on long-term compliance (Zimmerman et al., J Clin Psychiatry (2005): Why isn't bupropion the most frequently prescribed antidepressant? ).



  • Third Generation / Dual Mechanism Agents:
    There is evidence suggesting that there is a statistically significant difference favoring third-generation antidepressants (mirtazapine, venlafaxine, reboxetine (UK only)) over SSRIs on reducing depression symptoms, but the size of this difference is unlikely to be of clinical significance (NICE (2004): Depression: Management of Depression in Primary and Secondary Care [National Clinical Practice Guideline Number 23 (15 DEC 2004)]); also MHRA (2005): Safety of Selective Serotonin Reuptake Inhibitor Antidepressants [Letter to Healthcare Professionals (18 Feb 2005)]).



    Mitrazapine (Remeron)
    Mirtazapine is a noradrenaline and specific serotonin antidepressant (NaSSA) which blocks presynaptic alpha 2 receptors on both NA and 5HT neurones, and which also blocks postsynaptic 5HT2 receptors, implying less sexual dysfunction but possible worsening of the symptoms of OCD (obsessive compulsive disorder), and 5HT3 receptors, implying less nausea) receptors. In addition, mitrazapine can induce weight gain and sedation.

    The weight of the evidence base indicates that mirtazapine is equally efficacious with other classes of antidepressants, while appearing to have a statistical - though not clinical - advantage in terms of achieving remission. In addition, mirtazapine has a statistical advantage over SSRIs in terms of reducing depression symptoms, but the difference is not clinically important.
    However, there is strong evidence that patients taking mirtazapine are less likely to leave treatment early due to side effects.

    In sum, therefore, although mirtazapine is as effective as other antidepressants, it may have a clinical advantage in terms of reducing side effects likely to lead to patients leaving treatment early (NICE (2004): Depression: Management of Depression in Primary and Secondary Care [National Clinical Practice Guideline Number 23 (15 DEC 2004)]); also MHRA (2005): Safety of Selective Serotonin Reuptake Inhibitor Antidepressants [Letter to Healthcare Professionals (18 Feb 2005)]). Indeed, one recent head-on comparison (Versiani et al., CNS Drugs (2005): Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients) found mirtazapine to be as effective and well tolerated as fluoxetine in the treatment specifically of patients with severe depression, with mirtazapine producing significantly better improvements on sleeping assessment, but in contrast to fluoxetine, mirtazapine-treated patients experienced a mean weight gain of 0.8 +/- 2.7 kg compared with a mean decrease in weight of 0.4 +/- 2.1 kg for fluoxetine-treated patients.



    Venlafaxine (Effexor)
    Venlafaxine was the first of the new generation dual-action antidepressants. It inhibits the reuptake of both serotonin and noradrenaline, comparable to this activity in TCAs. Its activity "character" is dose-dependent: at the standard dose of 75 mg it is an SSRI, with dual action
    emerging at doses of 150 mg and above. At these higher doses it also inhibits dopamine reuptake. It presents has a broad range of side effects similar to the TCAs and
    SSRIs, and in addition can increase blood pressure at higher doses; it is for these several reasons associated with a high incidence of discontinuation symptoms.

    Venlafaxine at any dose is clinically equi-efficacious on all efficacy outcomes to other antidepressants, as well as on most acceptability and tolerability outcomes. However, there is some evidence that patients taking venlafaxine are more likely to leave treatment early due to side effects, particularly when low dose (<150 mg) venlafaxine is compared with fluoxetine, although for inpatients, those taking venlafaxine are less likely to stop treatment early compared to TCAs and SSRIs

    Note in addition that one small study of inpatients found that venlafaxine was superior to SSRIs on efficacy. On the other hand, in outpatients, there was some evidence for increased efficacy compared to other antidepressants, but only on response (NICE (2004): Depression: Management of Depression in Primary and Secondary Care [National Clinical Practice Guideline Number 23 (15 DEC 2004)]); also MHRA (2005): Safety of Selective Serotonin Reuptake Inhibitor Antidepressants [Letter to Healthcare Professionals (18 Feb 2005)]). The study by P. Vis (Ann Pharmacother (2005): Duloxetine and Venlafaxine-XR in the Treatment of Major Depressive Disorder: A Meta-Analysis of Randomized Clinical Trials) was the first to compare the efficacy and safety of duloxetine (Cymbalta) and extended-release venlafaxine (Effexor-XR) finding a favorable - but not statistically significant - trend in remission and response rates compared with duloxetine; dropout rates and adverse events did not differ between the two agents.

    Also, as noted above, the meta-analyses of Hansen et al. (Ann Intern Med (2005): Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder) did show a modest but statistically significant additional treatment effect for sertraline (Zoloft) and venlafaxine (Effexor) compared with fluoxetine (Prozac, Sarafem). Note however that the Berney's recent review (Dialogues Clin Neurosci (2005): Dose-response relationship of recent antidepressants in the short-term treatment of depression) found that the strategy of dose increase may be relevant for venlafaxine, in order to increase the number of responders.



    Duloxetine (Cymbalta):
    Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment of MDD (and for urinary incontinence). Studies support the efficacy and safety of 40-60 mg twice daily for the treatment of acute MDD (Dugan, Ann Pharmacother (2004): Duloxetine: A Dual Reuptake Inhibitor); Kirwin & Gören (Pharmacotherapy (2005): Duloxetine: a dual serotonin-norepinephrine reuptake inhibitor for treatment of major depressive disorder). Adverse effects have been of mild to moderate severity and are considered to be transient. Although cardiovascular effects (increased heart rate or blood pressure) may present, these do not appear to be clinically significant. Overall, duloxetine appears to be a well tolerated, safe and effective antidepressant. The review of Cowen et al. (Curr Med Res Opin (2005): Efficacy, safety and tolerability of duloxetine 60 mg once daily in major depression) found that multiple RCTs have demonstrated the efficacy of duloxetine 60mg once daily for the treatment of depression in both the short and long term, finding in addition that duloxetine significantly reduces the general aches and pains that frequently accompany MDD, all with an acceptable tolerance. The most frequently observed adverse events with duloxetine were nausea, dry mouth and somnolence; with respect to nausea, however, it was mild to moderate, and resolved rapidly with continued treatment (Greist et al., Clin Ther (2004): Incidence and duration of antidepressant-induced nausea: duloxetine compared with paroxetine and fluoxetine). Importantly, duloxetine did not appear to have a clinically significant effect on blood pressure.



  • Dose Escalation:
    Adli et al. (Eur Arch Psychiatry Clin Neurosci (2005): Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review) examined the issue of whether high-dose treatment, i.e., maximizing the dose of antidepressants, as is widely recommended in cases of non-response to medium-dose treatment, is scientifically supported, concluding that based on available data highdose antidepressant treatment of patients refractory to medium-dose treatment is recommended for tricyclic compounds but not for SSRI, with some data suggesting beneficial efficacy of ultra-high doses of the irreversible MAOI tranylcypromine. However Berney's recent review (Dialogues Clin Neurosci (2005): Dose-response relationship of recent antidepressants in the short-term treatment of depression) found that the strategy of dose increase may be relevant for venlafaxine, in order to increase the number of responders.

  • Acupuncture:
    Smith and Hay (Cochrane Database Syst Rev (2005): Acupuncture for depression) concluded that "there is insufficient evidence to determine the efficacy of acupuncture compared to medication, or to wait list control or sham acupuncture, in the management of depression. Scientific study design was poor and the number of people studied was small."



  • St. John's Wort:
    The latest evidence from high-quality systematic reviews demonstrates that St. John's Wort (SJW) is safe and effective for short-term (six to eight weeks) relief of mild to moderate depression in adults (see the distillation by Malaty of the Cochrane Review, in Am Fam Physician (2005): St. John's Wort for Depression; Linde et al., Cochrane Review (2005): St John's Wort for depression); see also Roder et al (Fortschr Neurol Psychiatr (2004: Meta-Analysis of Effectiveness and Tolerability of Treatment of Mild to Moderate Depression with St. John's Wort).

    However Linde (Br J Psychiatry (2005): St John's Wort for depression: meta-analysis of randomised controlled trials) - reviewing much the same literature of RCT's - finds that the evidence inconsistent and confusing, noting that larger placebo-controlled trials restricted to patients with major depression showed only minor effects over placebo, while older and smaller trials not restricted to patients with major depression showed marked effects. But the same author's (Linde & Knuppel, Phytomedicine (2005): Large-scale observational studies of hypericum extracts in patients with depressive disorders - a systematic review) review of large-scale observational studies concludes that SJW extracts are well tolerated and seem to be effective in routine treatment of mild to moderate depressive disorders.

    Against this, however, at least one later sufficiently powered RCT comparing SJW with paroxetine (Paxil) in the treatment of moderate to severe major depression - not mild to moderate, as in previous studies - found that SJW (as a hypericum extract WS 5570) was at least as effective as paroxetine and was better tolerated (Szegedi et al., BMJ (2005): Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's Wort): randomised controlled double blind non-inferiority trial versus paroxetine). In addition, the non-inferiority study of Gaspar et al. (Pharmacopsychiatry (2005): Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline) found SJW both not inferior to sertraline (Zoloft) for the treatment of moderate depression and well-tolerated, using a once-daily dose of 612 mg of hypericum extract given for up to 24 weeks. See also the noncomparative RCT prospective study of Uebelhack et al. (Adv Ther (2004): Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial) confirmed the clinical efficacy and tolerability of oral Hypericum extract STW 3-VI (Laif) 900 mg once daily for the treatment of moderate depression.

    Furthermore, a double-blind, randomized, placebo-controlled, multicenter clinical study (Gastpar et al., Pharmacopsychiatry (2006): Comparative Efficacy and Safety of a Once-Daily Dosage of Hypericum Extract STW3-VI and Citalopram in Patients with Moderate Depression: A Double-Blind, Randomised, Multicentre, Placebo-Controlled Study) demonstrated the non-inferiority and safety of a hypericum extract compared with citalopram (Celexa) in the treatment of moderate depression.

    Mannel (Drug Saf (2004): Drug interactions with St John's Wort : mechanisms and clinical implications) has reviewed preclinical and clinical evidence relating to drug interactions with SJW (Hypericum perforatum), finding sufficient evidence from interaction studies and case reports to suggest that St John's Wort may induce the cytochrome P450 (CYP) 3A4 enzyme system and the P-glycoprotein drug transporter in a clinically relevant manner, thereby reducing efficacy of co-medications, further finding that drugs most prominently affected and contraindicated for concomitant use with St John's Wort are metabolized via both CYP3A4 and P-glycoprotein pathways, and these include HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors (only CYP3A4), the immunosuppressants cyclosporin and tacrolimus, and the antineoplastic agents irinotecan and imatinib mesylate. Mannel speculates in addition that efficacy of hormonal contraceptives may be impaired, but this is based only on case reports of irregular bleedings and unwanted pregnancies.

    Despite this, Knuppel and Linde's safety review (J Clin Psychiatry (2004): Adverse effects of St. John's Wort: a systematic review) concludes that hypericum extracts are well tolerated and safe if taken under control of a physician who is aware of potentially relevant risks in specific circumstances.

    Finally, note that NICE (2004): Depression: Management of Depression in Primary and Secondary Care [National Clinical Practice Guideline Number 23 (15 DEC 2004)] and MHRA (2005): Safety of Selective Serotonin Reuptake Inhibitor Antidepressants [pdf] (Letter to Healthcare Professionals (18 Feb 2005)) concluded that St John’s Wort is more effective than placebo on achieving response in both moderate and severe depression, and on reducing depression symptoms in moderate depression, and that furthermore there appears to be no difference between St John’s Wort and other antidepressants, other than in moderate depression where it is better at achieving response, and in severe depression where it is less effective than low-dose antidepressants in achieving response. St John’s Wort appears more acceptable than antidepressants, particularly TCAs, with fewer people leaving treatment early due to side effects and reporting adverse events. Despite this, NICE and MHRA do not recommend SJW, largely consequent to the uncertainty about appropriate doses, variation in the nature of preparations and potential serious interactions with other drugs
    (including oral contraceptives, anticoagulants and anticonvulsants).




  • SAMe:
    Some studies of wide methodological quality have suggested that S-adenosylmethionine (SAMe) supplementation may be beneficial in the treatment of depression, leading Williams et al. (Clin Invest Med (2005): S-adenosylmethionine (SAMe) as treatment for depression: a systematic review) to undertake a systematic review, concluding that although the studies reviewed were short term, nonetheless there appears to be a role for SAMe in the treatment of major depression in adults.



  • Light Therapy and Seasonal Affective Disorder (SAD):
    Light therapy (as white bright light (10,000 lux, for one hour daily) has been suggested in treating mood disorders, especially those exhibiting seasonal variation (seasonal affective disorder, or SAD. Golden et al. (Am J Psychiatry (2005): The Efficacy of Light Therapy in the Treatment of Mood Disorders: A Review and Meta-Analysis of the Evidence) have undertaken a comprehensive systematic review and meta-analysis of randomized controlled trials, concluding that the balance of RCT evidence suggests that bright light treatment and dawn simulation for seasonal affective disorder is efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials, furthermore finding that bright light was efficacious and comparable in effect to most antidepressants even for nonseasonal depression. This latter result has been independently confirmed by Martiny et al. (Acta Psychiatr Scand (2005): Adjunctive bright light in non-seasonal major depression: results from clinician-rated depression scales).

    Unfortunately, despite rigorous demonstration of efficacy in high methodologically sound trials and reviews, light therapy remains severely underutilized in clinical practice (see the sober commentary of M. Moran (Psychiatric News (2005): Light Therapy Kept in Dark Despite Effectiveness)     .

  • Treatment-resistant Depression:
    Patients presenting with treatment-resistant depression are those whose depression symptoms have failed to respond to two or more antidepressants at an adequate dose for an adequate duration given sequentially; the term ’acute-phase non-responders’ captures those who have failed only one course of antidepressants.

    Treatment strategies deployed include:
    • Switching strategies
    • Venlafaxine for treatment resistant depression
    • Augmentation strategies:
       o antidepressant + lithium
       o antidepressant + anticonvulsants
          (lamotrigine, carbamazepine or valproate)
       o antidepressant + another antidepressant
       o antidepressant + pindolol
       o antidepressant +triiodothyronine (T3)
       o antidepressant + benzodiazepine
       o antidepressant + antipsychotic
       o antidepressant + buspirone



    Lithium and Suicidal Behavior Prevention
    The recent systematic review of Capriani et al. (Am J Psychiatry (2005): Lithium in the Prevention of Suicidal Behavior and All-Cause Mortality in Patients With Mood Disorders: A Systematic Review of Randomized Trials)     found that lithium is effective in the prevention of suicide, deliberate self-harm, and death from all causes in patients with mood disorders (including unipolar depression, bipolar disorder, schizoaffective disorder, dysthymia, and rapid cycling).

    Treatment Strategies - Efficacy Not Demonstrated:
    Along with the conclusions of NICE (2004): Depression: Management of Depression in Primary and Secondary Care [National Clinical Practice Guideline Number 23 (15 DEC 2004)] and MHRA (2005): Safety of Selective Serotonin Reuptake Inhibitor Antidepressants [Letter to Healthcare Professionals (18 Feb 2005)], the weight of the evidence base does not provide compelling evidence for the efficacy of either particular switching strategies or for deploying venlafaxine, although there is some evidence to suggest a clinical advantage for high dose venlafaxine (mean 269 mg) over paroxetine in terms of achieving remission, but insufficient evidence that this effect is evident with respect to response, mean endpoint scores or tolerability. Similarly, there is insufficient evidence to recommend the use of benzodiazepine augmentation of antidepressants. Yet Rush et al. (N Engl J Med (2006): Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression    ) tested whether switching to one antidepressant is more effective than switching to another after unsuccessful treatment for depression with a SSRI (citalopram), finding that approximately one in four patients had a remission of symptoms after switching to another antidepressant, although there was no significant difference between switching from citalopram to either sertraline, venlafaxine, or bupropion.

    In addition, augmentation of an antidepressant with carbamazepine, lamotrigine, buspirone, pindolol, valproate or thyroid (T3) supplementation is not motivated in the routine management of treatment-resistant depression.

    Treatment Strategies - Possibly Efficacious:

    - Augmentation of antidepressant + antidepressant:
    This can be considered for patients whose depression is treatment-resistant and who are prepared to tolerate the aggregate side effects. There is evidence for benefits from the addition of mianserin (Bolvidon, Norval, Tolvan) or mirtazapine (Remeron) to SSRIs, although mianserin should be used with caution, particularly in older adults, because of the risk of agranulocytosis.     The recent review of Dodd et al. (J Affect Disord (2005): To combine or not to combine? A literature review of antidepressant combination therapy) concluded that many antidepressants can be usefully combined especially if they engage separate mechanisms of action, and that antidepressant combinations clinically provide a useful resort in otherwise treatment resistant individuals.
    In this connection, Rubio et al. (J Affect Disord (2005): Reboxetine adjunct for partial or nonresponders to antidepressant treatment) in a prospective 6 weeks open-label study found that the strategy of combination with reboxetine (Edronax, Vestra), a selective norepinephrine reuptake inhibitor (SNRI) with use currently limited to Europe, may be an effective and well-tolerated tool in treatment-resistant patients who have failed to adequately respond to monotherapy with SSRIs, venlafaxine or mirtazapine. See also Fleischaker et al. (CNS Drug Review (2004): The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile), and Kadhe et al. (J Postgrad Med (2003): Reboxetine: A Novel Antidepressant).

    And although we know from field experience that clinicians often add a second medication to an initial, either ineffective or partially effective antidepressant, until the study of Trivedi et al. (N Engl J Med (2006): Medication Augmentation after the Failure of SSRIs for Depression) no randomized controlled trial has rigorously evaluated the efficacy of this augmentation approach. These researchers tested 851 adults with nonpsychotic major depressive disorder without remission despite a mean of approximately three months of citalopram (Celexa) therapy (with mean final dose, 55 mg per day), with 565 randomized to receive sustained-release bupropion (Wellbutrin) (at a dose of up to 400 mg per day) as augmentation and another 286 to receive buspirone (Buspar) (at a dose of up to 60 mg per day) as augmentation, finding both augmentations to be useful in clinical settings, but noting that augmentation with sustained-release bupropion offered the advantage of a greater reduction in the number and severity of symptoms and fewer side effects and adverse events.

    - Augmentation of antidepressant + venlafaxine:
    Venlafaxine should be considered for patients whose
    depression has failed to respond to two adequate trials of other antidepressants, with consideration given to high-dose therapy if required, provided patients can tolerate the side effects.

    - Augmentation of antidepressant + lithium:
    A trial of lithium augmentation should be considered for
    patients whose depression has failed to respond to several antidepressants and who are prepared to tolerate the burdens associated with lithium use.

    - Augmentation of antidepressant + phenelzine (MAOI):
    Phenelzine should be considered for patients whose
    depression has failed to respond to alternative antidepressants and who are prepared to tolerate the side effects and dietary restrictions associated with its use, although its toxicity in overdose must be considered when prescribing for patients at high risk of suicide.

    - Augmentation of antidepressant + aripiprazole
    Two clinical studies (by Simon & Nemeroff, J Clin Psychiatry (2005): Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder, and by Papakostas et al., J Clin Psychiatry (2005): Aripiprazole Augmentation of Selective Serotonin Reuptake Inhibitors for Treatment-Resistant Major Depressive Disorder) suggest that the atypical antipsychotic aripiprazole (Abilify) may be an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with standard antidepressant therapy, although confirming controlled studies are needed.

    - Augmentation of antidepressant + metyrapone
    Jahn et al. (Arch Gen Psychiatry (2004): Metyrapone as Additive Treatment in Major Depression) found that the anti-adrenal agent metyrapone (Metopirone) is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action, and providing a better treatment outcome compared with standard treatment while sustaining antidepressive effect.

    - Augmentation of antidepressant + sulphiride
    Uchida et al. (J Clin Psychopharmacol (2005): Combined Treatment With Sulpiride and Paroxetine for Accelerated Response in Patients With Major Depressive Disorder) found that the addition of the dopamine-mediated agent sulpiride (100 mg/d)) was safe and effective strategy for accelerating antidepressant response in patients being treated with paroxetine (10-40 mg/daily), with median times to response among responders alone for the combined treatment being 2 weeks as opposed to 6 weeks without sulpiride supplementation.

  • Adult MDD, Antidepressants and Suicide:
    Independent of the issue of suicide risk and SSRIs in children and adolescents, there has lately been raised comparable potential concerns re whether some SSRIs may cause the emergence or worsening of suicidal ideation in vulnerable patients (Cipriani, Barbui, and Geddes, BMJ (2005): Suicide, depression, and antidepressants). Three studies published in the 19 Feb 2005 issue of the British Medical Journal (BMJ) explore this issue critically.

    Fergusson et al (BMJ (2005):     Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials) in their systematic review of published RCTs comparing SSRIs with either placebo or other antidepressants in patients suffering from MDD and other clinical conditions found an almost twofold increase in the odds of fatal and non-fatal suicidal attempts in users of SSRIs compared with users of placebo or other therapeutic interventions, excluding tricyclics (where no differences were observed when overall suicide attempts were compared between users of SSRIs and TCAs). Note however that no increase in risk was seen when only fatal suicidal attempts were compared between SSRIs and placebo.

    Underscoring the importance of full weighting of the evidence by (regrettably rare) inclusion of unpublished studies, Gunnell et al (BMJ (2005):     Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review) included for review both published and unpublished RCTs submitted by pharmaceutical companies to the safety review of MHRA (Medicine and Healthcare products Regulatory Agency) of the UK comparing SSRIs with placebo in adults with depression and other clinical conditions, setting as outcome measures (1) completed suicide, (2) non-fatal self harm, and (3) suicidal thoughts. Their study found no evidence for an increased risk of completed suicide, with only weak evidence of an increased risk of self harm, and inconclusive evidence of an increased risk of suicidal thoughts.

    However, Martinez et al (BMJ (2005):     Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study) conducted a nested case-control study of information extracted from GPRD (General Practice Research Database), analyzing the risk of non-fatal self harm and suicide in patients newly diagnosed with depression and prescribed SSRIs or TCAs. They found in apparent contradiction to the other studies cited that the SSRI users were not at increased risk of suicide or non-fatal self harm in comparison with TCA users, although in younger patients (aged 18 or less), weak evidence indicated a higher risk of non-fatal self harm for those prescribed SSRIs

    There are some non-trivial methodological issues here, as wisely observed by Cipriani, Barbui, and Geddes in their editorial overview (BMJ (2005): Suicide, depression, and antidepressants). (1) RCTs typically included selected patient populations with short periods of time for follow-up, and hence these studies are not specifically designed to identify completed or attempted suicides (with this outcome variable reported only in a subgroup of studies). (2) Given that a diagnosis of MDD was not required for review inclusion, these trials necessarily represent different patient populations. (3) Although data pooling procedures across hundreds of trials increased the overall numbers, absolute numbers of patients attempting and committing suicide remained very low, leaving open the possibility that of a highly narrow margin of reporting or not reporting a few cases that may have completely changed overall outcome. (4) On the other hand, although the Martinez et al study analyzed a large number of newly depressed patients, the lack of randomization raises the problem of confounding by indication: doctors might preferentially prescribe SSRIs on safety grounds in patients at risk of suicide, and although the authors adjusted statistically for this potential confounder, the possibility that other known or unknown variables might have acted in unpredictable ways cannot be ruled out.

    Taking into account these methodological limitations, some lessons for clinical practice can nonetheless be drawn. Given the totality and weight of current evidence, there appears to date no clear relation between SSRIs and suicide, and together with available compelling evidence of efficacy of treatment of moderate to severe MDD with antidepressants, this should encourage the prescription dose-effective antidepressants for this patient population. At the same time, prescribers should be aware that SSRIs, like the earlier TCAs, may induce or worsen suicidal ideation and suicide attempts especially during the early treatment phases, likely consequent to the fact that of their particular propensity to induce agitation and activation at that time.

    To address this, prescribers should schedule frequent follow up, possibly also enlisting a supporting role for family and caregivers, during these at-risk early phases of treatment, and MDD patients should be advised against abrupt treatment withdrawal, given the adverse risk of discontinuation reactions. Note that these indications apply to adults MDD patients only: in children and adolescents the balance between benefits and harms appears to be negative (except possibly for fluoxetine (Prozac), the only presently FDA=approved agent in these applications), given minimal evidence of efficacy and accruing evidence of an association between exposure to SSRIs, and other antidepressant drugs, and the emergence of suicidal ideation and behaviors. Such risk, coupled with the lack of data on the long term impact of exposure of a developing brain to antidepressant drugs, discourages routine prescription of antidepressant drugs in children and adolescents.

SSRIs and Sexual Dysfunction