Dr. A Prabhu Dessai Consultant Psychiatrist
Panaji , Goa 403001
India
ph: 9096660920
The Psychopharmacology of Bipolar Disorder
Bipolar disorder has a prevalence of 1-3%, although some think it may be higher. Goodwin & Jamison (1990) estimate that approximately 1/3 of bipolar disorder is ever diagnosed, and only 1/3 of those diagnosed are in treatment, and only a small proportion of those in treatment are receiving optimal treatment. The peak ages of onset are 15-19, a fact that is well documented but under-appreciated. Going by the statistics, the average untreated bipolar patient will have the first episode of mood disruption at age 16 and 10 episodes by age 26! (Sachs) Considering the importance of this decade of development in establishing autonomy, vocational independence, and primary relationships outside the family, it is obvious that early diagnosis and treatment of bipolar disorder can have a profound effect on the course of a patient's life. In addition, the lifetime incidence of completed suicide in bipolar patients is on the order of 20% - this is an illness with a high degree of lethality, so our efforts to treat it should be vigorous and well informed.
Nothing here is to be regarded as a substitute for your own clinical judgment. This document is by its nature provisional and subject to revision. You should always determine for yourself whether anything you read here is accurate, current, or pertinent to the clinical situations you face. Non-clinicians should take this material as general information only, and not as specific clinical advice — any questions or concerns you have as a result of reading this document should be taken up with your own mental health treatment provider. I make no warrantee that the material presented here is without error or omission.
Diagnosis
DSM-4 diagnostic criteria
DSM-4 distinguishes between mood episodes and diagnosis. A manic (hypomanic) episode is a distinct period of abnormally euphoric, expansive or irritable mood lasting at least one week accompanied by at least 3 of the following (4 if mood is only irritable):
For a manic episode, there must be "marked impairment" in social or occupational functioning and/or hospitalization must be required for patient's protection. If this criterion is not met then the episode is hypomanic.
If the history includes one or more manic episodes, then the diagnosis is bipolar I. If the history includes only episodes of hypomania, then the diagnosis is bipolar II.
Cyclothymia is characterized by nearly continuous mild episodes of hypomania and depression that does not meet criteria for major depression, with no more than two months at a time of euthymia during an interval of two years.
Differential diagnosis and comorbid factors
When diagnosing bipolar disorder attention should be paid to ruling out external factors, such as hyperthyroidism, acute drug intoxication, delerium or brain injury, etc. The fact that the age of onset of bipolar disorder is usually in the first three decades, and that about 90% of all first episodes occur before age 40 suggests that anyone presenting with new-onset mania after age 40 with no prior depression should be strongly suspected of having an underlying medical condition or substance abuse as the prime causative factor.
Unipolar depression
Mania is not "the opposite" of depression
Akiskal and others have described a population of patients who fail to meet strict DSM-4 criteria for hypomania and propose a "bipolar spectrum" model. Some patients in the "bipolar spectrum" have predominantly dysphoric/depressed mood but do not respond to multiple trials of ADs; they may benefit from the addition of a mood stabilizer. McElroy, among others, suggests that a "dimensional" view is more useful; the degree or severity of depressive symptoms should be assessed independently of the degree and severity of manic symptoms. Although these reputable and respected researchers are voicing a commonly held viewpoint, this is an admittedly "gray" area nosologically.Consider bipolar spectrum diagnosis if patient has current depression with:
Always ask about bipolar symptoms when assessing depression.
DSM-4 diagnostic criteria mandate that major depression is excluded if a patient "has ever had an episode of mania or hypomania." The implication of this is that, strictly speaking, major depression is a diagnosis that can never be made with 100% confidence, since a significant proportion of those eventually diagnosed with bipolar disorder have an initial episode (or episodes) of depression. This is particularly true with early onset depression; one study (Geller et al 1994) found that over 30% of preadolescent children diagnosed with major depression went on to develop manic episodes. Early onset of depression (especially with comorbid anxiety disorder), family history of bipolar disorder, or multigenerational history of any mood disorder should heighten suspicion for bipolar rather than unipolar disorder. For instance, a teenager presenting with major depressive symptoms who has a first-degree relative with bipolar disorder should be strongly suspected of having bipolar not unipolar depression.
Inquire about all the criteria for manic episode listed above. DSM-4 criteria are actually very useful! Note: history of hypomania is often not reported by the patient but reported clearly by close relatives or friends. If you have a suspicion, get permission to talk to those who know the patient well. Tertiary experts on bipolar disorder uniformly insist on talking to family members as part of the evaluation process.
If "soft bipolar" symptoms are confirmed and the patient has had poor or equivocal responses to standard ADs, a trial of a mood stabilizer may be worth considering. Some of these patients, if not treated early, will develop more clear-cut hypomanic episodes as time goes on, clarifying the earlier suspicions regarding diagnosis.
A note about antidepressant-induced mania: The DSM-4 subcommittee reversed DSM-3 by excluding from the diagnosis of bipolar disorder those patients whose only symptoms of mania occur upon antidepressant treatment. There is now broad consensus that this was an error; approximately 80% of such patients will go on to have spontaneous episodes of mania or hypomania within 2 years (Sachs, Akiskal). Despite DSM-4, such patients should probably be treated as bipolar (I or II).
Schizophrenia
Historically, bipolar disorder has been confused with schizophrenia. Patients with severe mixed affective states can show prominent psychotic symptoms with no apparent "classic" euphoria, pressure of speech, etc., and can present as disorganized and thought-disordered, sometimes with florid paranoia. Adolescents especially sometimes present with mood-incongruent hallucinations, paranoia, and marked thought disorder, and turn out to have mixed-state episodes. Although affective symptoms usually are evident on exploration of history and mental status exam, they may be overshadowed by the psychotic picture. It is probably a good heuristic rule that any first-break psychotic patient (particularly if the index episode is in the mid-teens) should be tried sooner rather than later on a mood stabilizer (for instance, valproate), on the chance that a lifetime of neuroleptics might be avoidable.
Some question whether schizoaffective disorder is a distinct pathologic entity, but it continues to be useful as a diagnosis of exclusion at present.
Substance abuse
Approximately 60-75% (Sachs, Goodwin & Jamison) of the bipolar disorder clinical population have significant substance abuse (SA). Estimates vary widely (3% - 98% overall !) depending on whether rating scales or formal diagnostic criteria are used and whether the distinction is made between abuse and dependence. For females, bipolar II is associated with a higher incidence of alcohol abuse than bipolar I; for males the incidence is about equal. Cocaine abuse is associated with a several-fold increase in incidence of bipolar disorder; the rate of bipolar disorder in cocaine abusers may be higher than in any other category of substance abuse. Some increases in comorbidity exist in opiate abusing populations as well. Careful history can sometimes elucidate whether the SA is primary or secondary, but this is often obscure. SA is high both in depressed and especially in manic and mixed phases; some bipolar patients may cease drinking when depressed. The comorbidity may be due to genetic factors, attempts to "self-medicate," and/or a result of overall impairment of judgment. SA (especially cocaine or hallucinogens) can precipitate affective episodes and can alter the course of bipolar disorder by inducing switching. Bottom line: all bipolar disorder patients should receive a careful assessment of SA patterns and history.
With primary alcoholism and secondary affective disorder, affective symptoms usually remit after 2-4 weeks of sobriety (Akiskal). Persistence of affective symptoms longer than a month should heighten the suspicion of underlying affective disorder. Very early onset of SA suggests primary affective disorder - Famularo et al found 7 out of 10 patients with onset of alcohol abuse before age 13 had bipolar disorder. The prognosis for treatment of bipolar disorder is poorer for those patients who are also substance abusers. There is data suggesting that valproate is the preferred mood stabilizer in this population and that lithium is less effective.
Patients need to be educated about the relationship between the two disorders. AA or NA should be encouraged for those with substance dependence, but the patient should be "inoculated" against the attitude sometimes encountered in AA regarding abstaining from all "mind altering drugs" - more than one bipolar disorder patient has become manic or depressed after discontinuing mood stabilizers on advice from well-intentioned AA members. There is an AA pamphlet entitled The AA Member — Medications and other drugs, which clearly distinguishes between necessary and important prescription medications and self-administered drugs. Patients can be encouraged to obtain this pamphlet and refer to it if fellow AA members start pressuring them about their medications.
When both SA and bipolar disorder coexist - and they often do - each needs treatment in its own right. Successful treatment of bipolar disorder usually requires successful treatment of substance abuse.
ADHD
There is considerable overlap between symptoms of ADHD and those of bipolar disorder. The hyperactivity and distractibility of ADHD can be mistaken for the racing thoughts and increased motor activity of bipolar disorder. Comorbidity is high. In fact, Wozniak et al found 90% of bipolar children had comorbid ADHD and 19% of ADHD children had comorbid bipolar disorder. The differential is often obscure, but the following characteristics may be helpful. While bipolar disorder may have childhood onset, ADHD always does. Bipolar disorder usually shows a cyclic or episodic pattern (at least after age eight), while ADHD is relatively constant in its effects on attention and impulsivity. Bipolar disorder hyperactivity is usually more goal-directed compared to the scattered hyperactivity of ADHD. Sleep patterns in bipolar disorder show episodic alterations, particularly phase reversal, whereas ADHD patients tend to have more consistent difficulty, often with onset insomnia. When stimulants worsen the clinical picture bipolar disorder may be suspected, though the converse is not necessarily true, as sometimes bipolar patients improve with the addition of stimulants (see below).
Borderline personality disorder
There are some (Akiskal, Gunderson & Elliott) who have proposed that borderline personality disorder (BPD) should be seen as part of the affective spectrum, but others (e.g., Pope) who maintain that it is independent, though frequently coexisting with affective disorder. Although much of the overlap may be on the basis of the depressive features of BPD, Akiskal and his colleagues have emphasized the close linkage to bipolar disorder: in a series of 100 DSM-4 borderlines, 25% met criteria for bipolar II or cyclothymia on followup. Bipolar depression and the depressive mood of BPD patients can sometimes be distinguished by the latter's relative high day-to-day or even hour-to-hour variability (as opposed to distinct phases of depression with a beginning and an end), high reactivity, and lack of changes in sleep and appetite. An occasional atypical mixed or rapid cycling bipolar patient, however, will look very "borderline," with quite volatile and reactive mood. All too often, bipolar features can be missed in the "sturm und drang" of BPD, especially in adolescents, and care should be taken to rule out bipolar disorder before prescribing antidepressants. When racing thoughts are a clear symptom, a bipolar component should be suspected.
In sum, distinguishing the two disorders is problematic, and there is probably a subgroup of borderlines with "bipolaroid" (predominantly mixed state) features, for whom mood stabilizers are an important treatment modality. Lack of response to several antidepressants may be a clue here.
Treatment
Mood charting
The usefulness of mood charting for complex or treatment-resistant cases cannot be overemphasized. Some clinicians are mildly uncomfortable with using structured tools like this, feeling they tend to be a Procrustean bed onto which the treatment must be painfully fitted. While no checklist can capture a clinical picture perfectly, the advantages of using mood charting far outweigh its limitations if a patient is not responding to first-line treatments. Mood charting makes it possible to follow in great detail the patient's mood and relate it to a variety of variables in a way that would otherwise be impossible.
A sample mood chart is available here, adapted from one used by Sachs' MGH Bipolar Clinic. Charting assists in the tracking of medication use, mood, sleep, menstrual cycle, and other symptoms, as an invaluable aid for the psychopharmacologist's prescribing. It also becomes an ongoing reminder for the patient of the existence of his/her illness and the importance of monitoring and managing it with the team. Generally, patients rapidly come to appreciate its usefulness and become committed to filling out the charts faithfully. Failing to fill out mood charts is sometimes an early sign of trouble in the treatment alliance, though it can also result from anergic depression or disorganization.
A note about sleep. Sleep deprivation can precipitate mania. (It is a proven - if temporary - cure for depression.) Patients and their families should be educated about the high risk for mood disruption that is incurred when sleep hygiene is not maintained. A regular sleep/wake schedule should be followed, and alterations of sleep should be noted and reported. Mood charting is very useful for monitoring this.
Mood stabilizers
There is no agreed-upon definition of the term "mood stabilizer!" We all use the term, but it is nowhere officially defined. Sachs proposes: an agent that has efficacy in at least one of the primary treatment objectives (acute mania, acute depression, prophylaxis) that does not worsen an acute episode and does not increase affective switching.
In many cases more than one mood stabilizer will be necessary for full control of mood episodes. Serial trials of agents one after another is certainly the recommended way to begin treatment, but often adding a small dose of another agent can add considerably to therapeutic effect. Robert Post at NIMH has been an advocate of this approach, observing that at times using concurrent medications in lower doses can have synergistic therapeutic effects while avoiding side effects from any single med. Some patients do not fully respond until three or even four mood stabilizers are used concurrently, with full therapeutic doses of each.
Because polypharmacy is often necessary in bipolar treatment, an organized approach to the psychopharmacology of these patients is crucial. Except in very acute (usually inpatient) situations, one should not change or add more than one drug at a time, as this will obscure the evaluation of both response and side effects. Careful attention should be paid to drug interactions that affect dosing (e.g., CBZ lowers VPA levels, VPA raises LTG levels). Doses should be pushed to the maximum suggested or tolerated before concluding there is no benefit. Sufficient time should be given for any clinical improvement; pressure from the patient to move faster should be resisted as much as possible, since almost invariably this will complicate the picture with needless polypharmacy and/or premature conclusions of inefficacy. Keep in mind the rule of thumb that approximately five half-lives is required for a drug to achieve steady state — this becomes important for drugs with long half-lives, like zonisamide, which will not equilibrate until nearly two weeks after a dose change. Usually in mood disorders a minimum of 4 weeks after equilibration at maximal doses is necessary to have any confidence of full clinical effect.
An inadequate trial of a medication — either insufficient dose or too brief a course — is worse than no trial at all, since at best it is a waste of time and at worst it may permanently remove from consideration a potentially useful agent. "I already tried that, Doc -- it didn't help at all."
Mood charting is by far the best way of assessing response. Often patients report feeling "no better" globally when mood charting reveals that cycling frequency or amplitude is improving, which occurs typically well before any return to euthymia. In fact, months may be required for final stabilization of mood on the correct regimen.
A question that comes up often from patients is how long to stay on a mood stabilizing regimen. Current guidelines recommend 6-12 months after euthymia for bipolar I with 1-2 mild to moderate manic episodes (though some clinicians would be more ready to recommend longer term treatment even in this case), and indefinitely for bipolar I with >2 manic episodes or one manic episode if severe or with a strong family history of bipolar disorder. When stopping mood stabilizers, the taper should be done over 1-3 months. For bipolar II disorder, the Expert Consensus Guidelines recommend indefinite treatment after 3 episodes of hypomania or antidepressant-induced mania. The prevailing data suggests that there is a positive correlation between number of previous affective episodes and the development of treatment-resistance, so the decision to stop medications must be recognized as incurring significant long-term risk.
A note about mood cycling: Cycling does not necessarily imply phases of (hypo)mania followed by phases of depression. The cycling may consist solely of episodes of depression; with a past history of mania or hypomania, such patients are still bipolar, and the same criteria apply — the frequency of episodes is significant and should be monitored, and more than four episodes per year qualifies as rapid cycling. In addition, the pattern of cycling may be significant, since there is some evidence that with patients with either predominant depression or an "MDE" pattern (mania followed by depression followed by euthymia) the course and response to treatment may be different compared to those with "DME" pattern (see below).
A note about "compliance": Often a patient will present with hypomania announcing s/he stopped meds "because I didn't think I needed them any more." Don't mistake the cart for the horse in this situation - probe for the possibility that mild breakthrough hypomania resulted in some grandiosity that led to discontinuation of meds, rather than the other way around. If so, instead of simply restarting medications that were not fully effective, one should perhaps add or change mood stabilizers.
Accepted Mood Stabilizers
Lithium
Initial studies in the 1960's showed (Sachs 1998): Antimanic efficacy: four double-blind studies, n=116, 78% improved. Ten other controlled studies, n=413, 81% improved. Antidepressant efficacy: 11 controlled studies, n=269; 8 with lithium superior to placebo, 3 failed to show benefit (one was only a 10 day trial). Prophylactic efficacy: 10 controlled studies, n=514, all 10 show lithium > placebo, the overall rate of recurrence was lithium 37%, placebo 79%. Naturalistic studies show a very different picture!
More recent open retrospective studies fail to detect the benefit of lithium maintenance (eg, Mander 1989). Lithium monotherapy was found to be inadequate for most patients: an NIMH collaborative study showed 33% episode-free at 18-24 month follow-up; MGH followed up 100 unselected bipolar patients and found 4% (!) episode free at 1 year on lithium alone!
Baldessarini et al (2000) surveyed the literature and found that "[n]either reported recurrence rates nor average proportions of time ill nor patient improvement of 50% or more during lithium maintenance therapy in a stable clinic setting has changed significantly since the 1970s." It is hard to reconcile this study with the above data, however. One could speculate that over the years there has been a gradual recognition of less typical bipolar patients with variants of the disorder (rapid cycling, atypical bipolar II, etc) that are less amenable to lithium treatment. Further, the growth of antidepressant treatment may have contributed to this shift by promoting more rapid cycling in susceptible patients, and certainly some proportion of previously lithium-responsive patients have discontinued their lithium and become lithium non-responsive. Discontinuation of lithium for a patient previously responsive to it incurs a 50% incidence of relapse within 9 months (!) (e.g., Viguera et al); the recurrences may be more treatment-resistant than prior episodes and require switching or adding other mood stabilizers. In sum, there appears to be at least a subpopulation of bipolar patients now for whom lithium is not the treatment of choice. Nonetheless, lithium should not be underestimated as an effective first-line mood stabilizer. In addition, there is evidence that lithium-responsiveness is a genetic trait, so a family history of response to lithium should suggest this drug as a primary treatment.
Summary:
Attention should be paid to the possibility over time of subclinical hypothyroidism. The usual TSH screening picks up hypothyroidism once it has progressed to an endocrinologically significant point, but well before that a subtle functionally hypothyroid state can begin to compromise lithium responsiveness (see below under thyroid). If breakthrough hypomania begins to occur, it is probably worthwhile to consider low-dose thyroid augmentation, especially if the TSH is > 2.0.Lithium shows poor response in:
Valproate (eg, Depakote, Depakene)
VPA may now be the treatment of choice for acute uncomplicated mania and its continuation treatment. VPA is the current treatment of choice for mixed state and rapid cycling, and probably as well for psychotic mania and bipolar disorder with comorbid substance abuse.
Note: the paper by Bowden et al in Archives of General Psychiatry raises some controversial issues about VPA vs lithium in maintenance treatment. In their study, valproate did not differ from placebo in delaying recurrence of mood episodes, although it did show benefit over placebo in lower rates of discontinuation for a recurrent mood episode, and was superior to lithium in longer duration of successful prophylaxis. The study was criticized for the low relapse rate in its placebo group, suggesting that selection had been biased towards milder illness, partly because sicker patients may have been reluctant to risk getting placebo for a year. In addition, the study did not address the phenomenon of polypharmacy; in the real clinical world, optimal treatment may involve utilization of more than one mood stabilizer, and only maintenance monotherapy was examined, with severely limited "rescue" interventions. The long-term usefulness of VPA as part of a polypharmaceutical regimen has not been studied. For cyclothymia, VPA seems to be effective at surprisingly low doses, in one study 125-500 mg/day.
Summary:
The accepted position has for years been that VPA has poor efficacy for bipolar depression. It turns out that this was based in large part on a Finnish study. Close examination of the study suggests the evidence for this is shaky; the inclusion criteria allowed a huge percentage of patients with unipolar depression, a fact that was lost in the English translation of the report. There are more recent claims that VPA may have some antidepressant effect for bipolar (as opposed to unipolar) patients. Five small open trials of divalproex for bipolar depression showed a 30% response rate — not impressive, but perhaps not negligible. Whether this might be due to its effect on treating mood cycling is unclear.
Olanzapine (Zyprexa)
Olanzapine is now approved by the FDA for the treatment of mania. Although there have been reports of olanzapine inducing mania on occasion, it is proving to be a very effective mood stabilizer. Its major disadvantages are weight gain and sedation. Although the formal FDA approval is only for acute mania, there are now longer term studies demonstrating its usefulness for maintenance mood stabilization, and some indication (Sanger et al 2003) that it is useful for rapid cycling bipolar disorder. Olanzapine is proving to be an excellent mood stabilizer, but there is growing recognition of its role in causing the "metabolic syndrome" of obesity, elevated serum lipids, and insulin resistance, which must be addressed especially with long-term use.
Summary:
Carbamazepine (eg, Tegretol)
Evidence for CBZ's antimanic efficacy is not as robust as that for VPA, though it has been in use even longer than VPA for this purpose. It seems to have some antidepressant effects. It may be even more effective as a second mood stabilizer, though its tendency to induce CYP enzymes requires that blood levels of all agents need to be followed. Dosage should be titrated to serum levels, though the correlation between serum level and therapeutic effect is near zero in some studies. Note that this may mean that different patients may require differing serum levels for efficacy, not necessarily that serum levels in any given patient have no meaning at all. Apparently the new Tegretol XR form of carbamazapine will be submitted for approval by the FDA for acute mania.
Summary:
Lamotrigine (Lamictal)
Lamotrigine has just been approved by the FDA for "the maintenance treatment of adults with Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy." Although the approval refers to "mood episodes," the data are only convincing for prevention of depression — it does not do well at preventing recurrences of mania. Although there is data supporting its use in acute mania, it seems not to be as reliable for this as valproate, lithium, or olanzapine, and there have even been case reports of it causing mania. It may be useful for treating acute bipolar depression. It is generally less sedating than the other anticonvulsant mood stabilizers. Its major drawback is the risk of serious rash, requiring slow titration of initial dose, and its interactions with CBZ and VPA (see below). An FAQ is available online.
Summary:
ECT
ECT seems to be equally effective for acute depressive and acute manic episodes, and is more effective statistically than any drug for depression, whether unipolar or bipolar. Bilateral ECT seems to be more effective for bipolar patients, depressed or manic, though more recent experience suggests greatly suprathreshold unilateral ECT may be used. Generally, anticonvulsant mood stabilizers and benzodiazepines will be discontinued for ECT, though they may just be held the morning of treatment with bilateral ECT; lithium and/or neuroleptics (including clozapine) need not be, though lithium dose may also be held acutely to let levels drop because of concerns about increased neurotoxicity. Maintenance ECT for long-term control of bipolar disorder appears to be a viable treatment — see Vaidya et al.
Investigational mood stabilizers
These are rational options with less data as yet to back them up. Some of them are mainly of theoretical interest, others have some clinical experience or uncontrolled studies to support their use. None of them can be recommended as first-line agents, though lamotrigine, gabapentin, and topiramate are approaching that status. I include here even agents for whom the evidence of efficacy is very sparse; when a patient does not respond to first-line treatments one must try less accepted ones, since occasionally a less orthodox treatment can be quite successful.
Anticonvulsants
Oxcarbazepine (Trileptal)
Oxcarbazepine is a keto-analogue of carbamazapine. The modification to the molecular structure prevents it from being metabolized by oxidation to CBZ-10,11-epoxide, which is the metabolite that is thought to be responsible for much of the toxicity of CBZ. OCB is metabolized by conjugation rather than by oxidation, and largely excreted by the kidney. See e.g. Lloyd et al. It has been on the market for over 10 years in various countries. The neurologists that I have spoken to seem to regard it as exactly equivalent to CBZ for seizure control ("It's Tegretol without the toxicity"). The clinical efficacy for seizure control of OCB compares favorably with CBZ in clinical trials, and there are case reports of its efficacy for bipolar disorder, and a very small placebo-controlled 1983 study (interestingly, this study was one of the early favorable reports for the use of VPA in mania). More recently, other studies have compared OCB (favorably) to lithium and to haloperidol, and at the 2001 APA meeting Reinstein presented a poster reporting equal effectiveness compared to valproate for acute mania. See also the recent open label study by Gaemi et al 2003. There have been no instances of marrow suppression in 7000 cases according to one citation. Compared with CBZ, P450 enzyme induction is greatly reduced; there is only a moderate induction of CYP3A4 and other isoenzymes seem not to be affected. It seems to be less prone to causing cognitive impairment than CBZ (see Grant & Faulds 1992). When switching from CBZ to OCB, one should be aware that the previous induction of CYP enzymes will be considerably decreased, and as a result the serum levels of other drugs may rise. The only medical issues of note is its occasional side effect of hyponatremia.
Summary:
Gabapentin (Neurontin)
GBP is an anticonvulsant drug particularly notable for its relative safety and lack of interactions with other drugs. Its use in bipolar disorder is based on clinical impressions of efficacy, usually as an adjunctive agent; it has not at this point been adequately established as a primary mood stabilizer. In fact, Parke-Davis sponsored a study preparatory to an FDA application for use as a mood stabilizer and found no efficacy above placebo (the FDA application has not been pursued, but a related compound is being looked at which may have greater efficacy). For many patients it seems to have significant benefit in combination with other agents, e.g., in reducing depression — but not mania — in mixed states (see Schaffer & Schaffer 1999). It cannot be recommended in most cases as a sole treatment. The prevailing clinical impression is that GBP appears to have fairly definite antianxiety effect. It also works well in lower doses in some patients for sleep, as an alternative to trazodone. An FAQ is available online.
Summary:
Topiramate (Topamax)
Topiramate is yet another anticonvulsant with mood stabilizing effects for some patients (see, eg, Marcotte 1998, McElroy et al 2000, Guile & Sachs 2002). It blocks sodium channels, enhances GABA, inhibits non-NMDA (kainate/AMPA) receptors, and inhibits carbonic anhydrase; which of these effects is most important for anti-seizure or mood stabilizing effect is not clear. It may also have some efficacy in anxiety, bulimia, and PTSD. It has been reported to cause depression, but the incidence of this is undetermined. Some clinicians — notably Alan Schatzberg (personal communication) — are now trying low doses (25-75mg/d) of TPM as an adjuctive treatment to counteract the tendency toward weight gain from VPA, with occasional success. The latest data on its antimanic effect is disappointing; nonetheless, it could be tried as a second-tier mood stabilizer when more reliable ones fail. One study finds it quite effective in preventing relapse in alcohol dependence. An FAQ is available online.
Summary:
Tiagabine (Gabatril)
Tiagabine is yet one more anticonvulsant with possible mood stabilizing properties. It is a selective GABA reuptake inhibitor. Although a small open trial failed to find any therapeutic effect in acute mania, there are some reports (eg, Kaufman 1998, Suppes et al 2002) of it being effective in augmentation of mood stabilization. Dosage seems to be 4-8mg/day; in doses of 12-16mg/day it tends to cause cognitive impairment.
Zonisamide (Zonegran)
Zonisamide has been in used in Japan as an anticonvulsant (Excegran) since 1989. Its precise mechanism of action remains obscure, although it has been noted to have calcium channel blocking (CCB) activity. ZNS is long-lived, with a elimination half-life of 63-68 hours. Its renal/hepatic metabolism is roughly 85%/15%. It does not exhibit inducing or inhibitory effects on CYP enzymes in the mouse and does not autoinduce its own metabolism, which is at least partially through CYP3A4, for which it is a substrate. It is a sulfonamide derivative, so patients allergic to sulfonamides should probably avoid it. There are small uncontrolled series in which ZNS was found to have definite anti-manic effect. Recommended initial adult dosage in Japan is 100-200 mg/d, increased if necessary to 200- 400 mg/d, up to a maximum of 600 mg/d. See the preliminary package insert for more details, and also this article from 1994.
Levetiracetam (Keppra)
Levetiracetam is an anticonvulsant approved in the US in late 1999. There are now anecdotal reports of its action as a mood stabilizer, though no published accounts or studies are available in humans (one animal study suggests promise for bipolar disorder). It is a novel anticonvulsant, unrelated chemically to other drugs in the class. It has no known interactions with any other drugs, and low protein binding, and its mechanism of action is unknown but doesn't seem to involve GABA pathways or any common neurotransmitter kinetics, nor does it affect benzodiazepine receptor sites. It is largely excreted by the kidney, and undergoes little if any hepatic metabolism; it does not affect CYP enzymes. Dosage for anticonvulsant purposes is 1000-3000mg/day in divided doses. See this webpage for some more details. It is being tried in both adults and children for treatment-resistant bipolar disorder, and it seems to have some efficacy in selected patients. Stay tuned for more as it develops.
Adrenergic blockers
Clonidine, guanfacine, propranolol
Several small studies have suggested that high dose propranolol has antimanic effect. Similarly, clonidine (actually an alpha-2 agonist which functionally decreases NE tone) in doses of 0.45-0.75mg/day was found to have acute antimanic effect, with less sedation than neuroleptics. One study used clonidine for maintenance treatment with good effect over three years in four out of seven cases. Guanfacine has been reported to actually induce mania, especially in children with family histories of bipolar disorder; it has also been found to raise valproate levels.
Ca-channel blockers
Verapamil, nifedipine, nimodipine
Nimodipine is a dihydropyridine Ca-channel blocker. Post (1998) reports "clinically important responses in 10 of the first 30 patients exposed to nimodipine monotherapy, and in many instances this responsivity was confirmed in B-A-B-A (on-off-on-off) double-blind clinical trials. However, in the majority of instances, the response was less than complete, and required augmentation with carbamazapine (4 of 13 patients showed a good response to this augmentation regimen) and other agents as well." This response faded in three patients when they were shifted to the less expensive verapamil; isradipine and amlodipine, both dihydropyridine-type Ca-channel blockers, seemed to preserve the response. Research on nifedipine has shown inconsistent effects on mood stabilization. Post suggests that dihydropyridines may have specific utility for bipolar disorder. Nimodipine does not cause weight gain or tremor, and incidence of GI side effects is low. It does not seem to cause cognitive dulling, and may even sharpen cognition in some patients; it increases CSF somatostatin levels (permanently reduced in patients with Alzheimer's and transiently reduced in patients with depression and MS). Dosage is 30 mg BID initially, then 30 mg QID; one case report used 270mg/day. Needless to say optimal dosing remains to be established.
Acetazolamide (Diamox)
Acetazolamide is a carbonic anhydrase inhibitor. One paper (Hayes 1994) reported using acetazolamide in treatment refractory bipolar patients, and it has been used since with occasional success. In the 1994 study, seven of 16 patients had positive results, some maintained over 2 years. "[A]ll of the responders were either in a depressive phase or in a rapid-cycling phase of a bipolar illness and... all had experienced partial positive response to at least one other anticonvulsant and were being maintained on anti-convulsant therapy when the response occurred." Dosage used for glaucoma and altitude sickness is 375-1000 mg/day divided into two doses, dosage for use in bipolar disorder is not yet well established.
Cholinesterase inhibitors
Burt et al (1999) reported on a small open trial of donepezil (Aricept) as an adjunctive treatment for acute manic and mixed states. Six of 11 had "marked" improvement and 3 more had "slight" improvement. Five of the six marked responders experienced improvement within two weeks or less. Although one patient did not tolerate the medication, side effects were generally mild. Presumably, controlled studies will follow. Meanwhile, this might be worth trying in some non-responders. Note that in one study looking at its efficacy in psychotropic-induced memory loss (it was helpful!), two bipolar patients became manic, so be alert for switching.
Mexiletine (Mexitil)
One study (Schaffer et al) found mexiletine, an anti-arrhythmic drug with anticonvulsant activity, to be helpful in rapid-cycling bipolar disorder. To quote from the results section of the medline abstract:
"Thirteen subjects (10 female, 3 male), mean age 41 years (S.D.=7.6), and mean duration of illness 20 years (S.D.=7.7) completed the study. The dose range of mexiletine was 200-1200 mg/day. Full response (>/=50% reduction in BMS) was seen in 46% of the subjects, and a partial response (25-49% reduction in BMS) in 15%. Of note, 5/5 subjects with a mixed or manic state demonstrated a full or partial response."
This was a small open trial, with the attendant limitations, but may point to another mood stabilizing agent to try in treatment-resistant cases.
Adjunctive treatments
Typical Neuroleptics
Naturalistically, 30-40% of bipolar patients receive chronic neuroleptic treatment. Why? 20 studies since 1970 show high incidence of psychotic symptoms in mania: delusions 48%, hallucinations 15%, Schneiderian first-rank symptoms 18%, prior history of psychosis 58%. The earlier the onset of first episode the greater the incidence of psychotic symptoms (Rosen et al 1983). Most bipolar patients will respond to lowish doses (e.g., haloperidol 2-10 mg/day) especially if combined with benzodiazepines.
Note that if psychotic symptoms occur during hypomania, DSM-4 classifies the episode as severe and requires changing the diagnosis to mania even if other symptoms are mild. Implication: usually if a bipolar patient ends up on neuroleptics, the diagnosis will be bipolar I not bipolar II. If chronic neuroleptics are needed, the question of schizoaffective disorder arises. It is still not clear if schizoaffective disorder is really a separate illness in any sense - for instance, what if some "schizoaffective" patients end up responding in a few years to some new mood stabilizer currently unavailable and turn out not to need neuroleptics? Will we then conclude they were bipolar after all? Or that the "mood stabilizer" has neuroleptic properties? This is a murky area. Given the risks of long-term neuroleptic use, any bipolar patient who seems to need chronic neuroleptics probably should be considered for a more vigorous mood stabilizing regimen, since there is a reasonable chance that the psychotic symptoms represent inadequately treated affective disorder.
Acute phase indications for neuroleptics:
Maintenance phase indications for neuroleptics:
Neuroleptic downside:
Adverse effects: acute EPS, akathisia, tardive dyskinesia (incidence may be higher in affective disorders and elderly women), seizure, NMS. Mukherjee et al (1984) report a high incidence of abnormal neurological signs in bipolar patients with high neuroleptic exposure, and suggest a causal relationship. (Note that this was an era when bipolar patients were universally treated with lithium, which has been found to heighten neurotoxicity in combination with neuroleptics; other mood stabilizers may not do this.) Negative impact on course of illness: possible increase in cycle frequency, increased incidence of depression (both post-manic and during maintenance).
Sachs suggests using neuroleptics as follows:
Atypical neuroleptics
There is less controlled data on atypical neuroleptics, but all of them now have data supporting their use in acute mania. Studies suggest they have a superior side effect profile and efficacy equal to or better than standard neuroleptics. Some of them, however, can occasionally induce or worsen the symptoms.
Bipolar Affective Disorder
Bipolar disorder is a mental illness characterized by the presence of at least one manic, mixed, or hypomanic episode. The presence of a Major Depressive Episode is very common in the lifetime of individuals with Bipolar Disorder (more than 90% of these individuals have at least one Major Depressive Episode in their lifetime), but it is not necessary to experience a depressive episode.
Some facts about bipolar disorder
Bipolar disorder affects males and females at equal rates.
The peak age of onset of bipolar disorder is between the ages of 15 and 25.
Bipolar Disorder is a mental illness characterized by the presence of one or more of the following:
Only one of these episodes needs to occur just once during the lifetime of an individual in order for that individual to be considered as suffering from Bipolar Disorder.
The presence of a Major Depressive Episode is very common in the lifetime of individuals with Bipolar Disorder (more 90% of these individuals have at least one Major Depressive Disorder in their lifetime), but it is not necessary. There are individuals with Bipolar Disorder who do not have a history of Major Depressive Episodes in their lifetime.
Subtypes of Bipolar Disorder
Bipolar I Disorder
To be diagnosed as Bipolar I, an individual must have at least one manic or mixed episode (lasting for at least a week) within his or her lifetime. A depressive episode is not required in order to warrant a dianosis of Bipolar I, although most people usually have multiple depressive episodes.
Bipolar II Disorder
In order to receive a diagnosis of Bipolar II Disorder, one must have had at least one hypomanic episode and at least one depressive episode within his or her lifetime. The patient must have never had a manic episode.
Mood Disorders Predict Later Substance Abuse Problems
People with manic symptoms and bipolar disorder type II are at significant risk of later developing an alcohol abuse or dependence problem, a long-term study conducted in Switzerland confirms. The study was published in the January 2008 issue of the Archives of General Psychiatry.
http://www.nimh.nih.gov/science-news/2008/mood-disorders-predict-later-substance-abuse-problems.shtml
An Overview of the Soft Bipolar Spectrum
By Arnold L. Lieber, MD
Bipolar I Disorder (manic depressive illness with or without psychosis), bipolar II disorder (episodes of major depression alternating with episodes of hypomania which are not severe enough to result in impairment of function) and cyclothymic disorder (brief and attenuated episodes of depression and hypomania sometimes known as minor cyclic mood disorder) are defined by explicit criteria sets in the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM- IV). Together, these three conditions are thought to have a lifetime prevalence of 3% to 4% of the general population. In recent years, clinical research has begun to validate the observations reported by experienced practitioners of clinical psychopharmacology - that a much larger group of patients demonstrate milder and/or atypical forms of episodic mood disturbances ( sub threshold bipolar disorder ). These patients are frequently resistant to standard antidepressant therapies, and sometimes their conditions are worsened by drug treatment with antidepressants. Efforts at clinical subtyping of the so-called soft bipolar spectrum are ongoing; up to this time such patients have fallen into the DSM-IV diagnostic category of Bipolar Disorder, NOS (not otherwise specified). If we include these patients with the three DSM-IV bipolar subtypes, the lifetime prevalence approaches 5% to 8 % of the general population. This is a far cry from the 1 % prevalence for manic depressive illness postulated by several large scale epidemiological surveys conducted by academic consortiums.
BEYOND DSM-IV
Any experienced practitioner of clinical psychopharmacology will attest to the fact that a majority of patients presenting in office or outpatient settings with symptoms of mood disturbance, anxiety and/or depression do not meet strict DSM diagnostic criteria. Their symptoms often do not conform to the time constraints required and they tend to fluctuate over time. Anxiety and depression are likely to have atypical manifestations. Hypomania, when present, tends to be of the dysphoric (irritable) variety rather than the euphoric hypomania described in the DSM. Many of these patients have previously been started on antidepressants or anxiolytic drugs by their primary care physicians or by other psychiatrists. Either they have failed to respond to antidepressant trials (antidepressants are now commonly used for both anxiety and depression), or else they have had only a partial response. Sometimes the antidepressant treatment has worsened the depression or precipitated an episode of euphoric or dysphoric hypomania. Some patients present taking high doses of benzodiazepine tranquilizers, which no longer contain their anxiety. All of the above described patients populate the soft bipolar spectrum.
Presenting Symptoms
* Episodic mood instability - these patients manifest lifelong episodes of mood swings starting around adolescence. The mood shifts unpredictably among several distinct mood poles: brief depressions lasting hours to one or two days, brief euphorias, brief dysphoric or irritable episodes, brief paranoid episodes, episodes of rage or intense uncontrollable anger, episodic anxiety equivalents (panic attacks, phobias or obsessive ruminations ). This multiplicity of mood options begs the very issue of bipolarity. It appears that multipolar mood disorder might be a more accurate designation for the soft bipolar spectrum.
* Episodic atypical depression - bipolar depressions can manifest the entire gamut of endogenous, nonendogenous and/or atypical depressive symptomatology, and they are always recurrent over time. Soft bipolar depressions usually show atypical depressive features. Patients are mood responsive, which means that they respond to favorable circumstances with a temporary lifting of the mood that can last hours to a day or two before returning to the depressed state. Other symptoms may include eating too much, sleeping too much, feeling worse towards evening and intense tiredness or lethargy. Anxiety and its subtypes (phobias, panic attacks, OCD) frequently co-exist with atypical depression, as does episodic mood instability. There are a number of atypical depressive subtypes that are distinguished by special features. Since they are often episodic and associated with mood instability, they should be viewed as part of the soft bipolar spectrum. Included are the following: seasonal affective disorder - winter-onset atypical depressions; premenstrual dysphoric disorder - atypical depression associated with irritability, mood swings and dysphoria which occurs a week to ten days on either side of the menstrual period; hysteroid dysphoria - atypical depression mainly in women with histrionic personality features, whose episodes are precipitated by romantic rejection; abulic depression - atypical depression with a deficit syndrome ( apathy, amotivation, lack of will power, lack of energy, lack of pleasure in life, emotional blunting ).
* Hypomania - hypomania is of two types, euphoric and dysphoric or irritable. It is also of two durations, episodic and protracted or characterologic. Bipolar spectrum patients usually show episodic dysphoric hypomania. Euphoric hypomania feels good and is sometimes productive, but dysphoric hypomania produces irritability, emotional discomfiture, impulsiveness, temper dyscontrol and impaired judgment. It tends to interfere with interpersonal relationships and to limit productivity at work. There is a sense of inner speeding combined with restless over activity and racing thoughts, which can lead to a state of desperation. The hypomania frequently alternates with episodes of depression, and mood instability is almost always present. Sometimes brief euphoric episodes are added to the mix. The triad of irritable episodes alternating with rage episodes and paranoid episodes is characteristic of dysphoric hypomania.
* Mixed states - mixed bipolar disorder [ the simultaneous occurrence of both depressive symptoms and mania/ hypomania ] and rapid cycling bipolar disorder [ the patient experiences frequent switches from depression to mania/ hypomania and back ] often produce diagnostic confusion for treaters and treatment resistance for patients. These mixed states are found in bipolar I, bipolar II and bipolar spectrum disorders. They are more common in women and are often associated with thyroid abnormalities, lack of response to lithium (the standard treatment for bipolar I disorder) and antidepressant-induced worsening of symptoms. Outpatient diagnosis of these conditions is difficult at best, even after a detailed history is obtained. Diagnosis of mixed states is most likely to be made by a skilled diagnostician after a patient fails to respond to outpatient treatment or becomes worse on antidepressant medications and is subsequently admitted to the hospital for closer observation. Misdiagnosis of these conditions is all too common, leading to delays in effective treatment and a higher risk of suicide.
THE PROBLEM OF CO MORBIDITY
Comorbidity means the simultaneous existence of two or more medical conditions in the same patient at the same time. A high percentage of bipolar mood disorders, perhaps more than 50 %, are comorbid with other medical and/or psychiatric conditions. This can complicate both diagnosis and treatment. Significant comorbid conditions and how they may impact bipolar spectrum disorders are presented:
* Thyroid disorders - any thyroid disease that results in either a hyperthyroid or a hypothyroid clinical state can interact adversely with bipolar mood disorders. Hyperthyroidism can resemble hypomania/ mania and it can worsen pre-existing mania/ hypomania. Hypothyroidism can resemble clinical depression and it can cause pre-existing depression to be unresponsive to antidepressant medications. Treatment with lithium can produce hypothyroidism, which then interferes with the effectiveness of psychotropic medications. Subtle or subclinical hypothyroidism is often associated with the development of mixed and rapid cycling bipolar disorders. If present, it must be compensated for in order to successfully treat the mixed state. In general, the co-existence of a thyroid disorder, unless recognized and adequately treated, will interfere with effective treatment of bipolar disorder and also of major and minor depressions.
* Substance abuse - approximately 50% of all patients with bipolar disorder will experience significant alcohol and/or drug abuse at some point during the lifetime course of their bipolar illness. This is a serious problem since the use of any intoxicating substance has psychoactive effects on the brain and can worsen the bipolar condition. Additionally, substances (including excessive caffeine and nicotine use) interfere with effective treatment of the mood disorder. Alcohol and drugs can mimic both depression and hypomanic states, but they do not cause bipolar illness. Substance use may, however, unmask a pre- existing depression or bipolar disorder. Bipolar mood disorders can and frequently do give rise to secondary alcohol and substance abuse. It is quite common that adolescents and adults who have not yet been diagnosed, attempt to self-medicate their unpredictable and uncontrollable mood swings with whatever is readily available - alcohol, marijuana, amphetamines, cocaine, opiates. By the time they reach evaluation, these patients are manifesting two separate and related conditions that feed upon one another, vastly complicating the treatment of both. I will not undertake the treatment of co-morbid bipolar/ substance abuse patients until they have undergone detoxification and have been able to remain substance-free for thirty days. The bipolar illness will not yield to treatment until the body is thoroughly cleansed of all intoxicating substances. The saving grace here is that once the underlying bipolar disorder is adequately controlled, the desire and craving to use substances is often dramatically reduced and sometime eliminated entirely.
* Attention deficit hyperactivity disorder (ADHD) - this condition is most frequently associated with hyperactive children, who have great difficulty sitting still and paying attention in school. It is now known to often persist into adulthood and its symptoms may overlap with those of adults diagnosed with bipolar spectrum disorder. Overlapping symptoms may include restlessness, motor hyperactivity, easy distractibility, impulsiveness, inability to concentrate or focus attention and temper dyscontrol. ADHD tends to be present continuously, whereas bipolar conditions are almost always episodic. The two conditions can co-exist in the same patient, although the incidence of their co morbidity is unknown. Stimulants such as methphenindate (Ritalin), which are the treatment of choice for ADHD, tend to worsen the symptoms of bipolar spectrum disorder. Antidepressants, especially the older tricyclic drugs such as desipramine and nortriptyline, may be effective for both disorders, frequently in combination with a mood stabilizing medication.
* Borderline personality disorder - these patients have elements of any or all of the DSM- IV personality disorder categories combined, leading to a stormy and unstable lifestyle. They tend to be overly dramatic, to have intense but unstable relationships, to be acutely sensitive to abandonment, to place unrealistic demands upon their families and their treaters and to exhibit self-defeating and often self-destructive behaviors. Substance abuse, self- mutilation and suicidal behaviors are frequently present. At one time they were considered to be the most difficult and demanding of all patients, and many books have been written detailing special techniques of psychotherapeutic treatment. In recent years it has become apparent that a high percentage of these patients have co morbid bipolar spectrum disorders. This has proved to be a very important development for these patients. Those who are able to comply with psychopharmacologic management, and achieve mood stabilization, have been found to become amenable to standard psychodynamic psychotherapy. I have found that about 75 % of these patients will respond to combination pharmacotherapy using a serotonin reuptake inhibiting (SSRI) antidepressant, a mood stabilizer and an atypical antipsychotic medication such as olanzapine or risperidone. Once the mood has become stable, they can then benefit from competent psychotherapy to deal with their emotional backwash. The prognosis (future outlook ) for patients who are accepting of this treatment approach is much better than it was a few years ago. Today they are often able to get better and to lead normal lives.
* Personality disorders - many patients with bipolar illness will demonstrate some features of the various personality disorders described in DSM-IV during episodes of mood disturbance. I have encountered bipolar patients showing excessive dependency, passive aggressiveness, histrionic traits, paranoid features, narcissism or extreme self-centeredness, hypochondriasis and manipulative antisocial traits. Usually, when they are effectively treated for their bipolar conditions, these characterological features become insignificant or may disappear entirely. However, when major character pathology co-exists with bipolar disorder, treatment is often problematic. Patients with fixed personality disorders tend to be demanding, defiant, manipulative and self-defeating, often undermining the efforts of their treaters. They often abuse alcohol and drugs and they tend to be noncompliant with efforts to treat them, both pharmacologically and psychotherapeutically. They understand why they might need and benefit from treatment, but most crystallized personality disorders present an insurmountable obstacle to effective treatment. Bipolar conditions have a high prevalence in prison populations.
DIAGNOSTIC CONSIDERATIONS
Bipolar I and II disorders are not difficult to diagnose, given an acquaintance with DSM-IV diagnostic criteria and the clinical presence of clear cut mania or hypomania. When bipolar disorder presents initially with depression, the diagnosis is often not made unless and until a later episode of mania or hypomania appears. The clinician should have a high index of suspicion for bipolarity when the depression is episodic and there is a family history of bipolar illness or its concomitants. These include alcoholism, drug abuse, uncontrolled episodes of rage and/or violence, suicide attempts, postpartum depression, psychiatric hospitalizations for depression or psychotic states. The diagnosis of bipolar spectrum disorder is more difficult. This is not surprising when one considers the above noted comorbidities, the nuances of the various clinical subtypes and their differing symptom sets, the rapidly fluctuating mood poles and the presence of mixed states. The basic mood disorders evaluation consists of the following elements: detailed history of the presenting symptoms, history of previous episodes and their response to treatment, family psychiatric history, medical history including results of a recent physical examination, a listing of all medications taken presently and during the past month, a listing of any psychotropic medications used now or previously including the patient's response or non-response to these drugs and a current mental status examination. It is advisable to administer a structured clinical interview designed to detect and diagnose mood disorders. Several are now available and some are structured to detect subtypes based on certain symptom clusters. Some laboratory tests may also be helpful. The TRH Stimulation Test will assess for the presence of clinical or subclinical hypothyroidism; it has also proved helpful in the discrimination of unipolar from bipolar depressions. All the brain imaging technologies have been used to examine groups of depressives. They have shown promise in the delineation of brain changes specific to certain depressive states, including bipolar depressions. Included here are CAT scans, MRI scans, PET scans, SPECT scans and quantitative EEG with auditory average evoked potentials (brain mapping). These tests are expensive, they are not always available to psychiatrists and their findings are considered by many to belong in the realm of research. They hold promise for the emerging objectification of psychiatric diagnoses.
TREATMENT CONSIDERATIONS
For a comprehensive review of the treatment of bipolar disorders, the reader may wish to access an excellent website maintained by Peter M. Brigham titled The Psychopharmacology of Bipolar Disorders.
I will present a personalized approach to the assessment and treatment of bipolar spectrum disorders. It may differ from that of other practitioners, but we psychopharmacologists tend to become intuitive and sometimes creative alchemists in our search for effective treatments. As a specialist in treatment refractory mood and anxiety disorders, most of the patients I see have failed to adequately respond to one or more trials of antidepressant and/or anxiolytic medications. They undertake an assessment that includes a specially designed clinical interview for mood and anxiety disorders, a structured symptom inventory administered and scored by computer, depression and anxiety symptom severity rating scales, quantitative EEG with averaged auditory evoked potential ( P-300 ) testing and , when indicated, a TRH Stimulation Test. Around 75% of my patients turn out to have bipolar spectrum disorder. If they have been taking benzodiazepines I inform them that they will be tapered off these drugs concomitant with their treatment. If they have recently abused drugs or alcohol , I defer treatment until they have been substance-free for thirty days. If they have complicating medical illnesses or mixed states, or if they are on very high doses of benzodiazepines (Ativan, Xanax, Valium, Klonopin, Tranxene, etc.), I usually insist on inpatient stabilization in a hospital setting that is designed for rapid detoxification and psychopharmacological stabilization. All patients are counseled regarding the importance of strict compliance with medication instructions and the need for long term follow-up monitoring. Some will require individual or group psychotherapy, but that determination is generally made after pharmacological stabilization has been achieved. The treating physician should be easy to reach by telephone. Patients may need reassurance during the early stages of treatment when they are more likely to experience transient medication-related side effects.
Patients who have been diagnosed with bipolar spectrum disorder and present with predominantly anxiety or depression symptoms are started initially on an SSRI antidepressant (Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro). I have found these drugs to have excellent anti-anxiety and antidepressant efficacy and also to be reasonably good mood stabilizers. I monitor the patients every one or two weeks until they are stabilized. If symptoms of hypomania occur during the course of treatment, I add a mood stabilizer such as Depakote, Tegretol, Lamictal or Topamax, all of which are also anti-epileptic medications. If the patient fails to respond to the SSRI within four weeks or is unable to tolerate it due to side effects, I will switch to a dual neurotransmitter antidepressant (Effexor, Welbutrin, Remeron, Serzone, Cymbalta). Once the patient is mood stable and without symptoms, I monitor at one to three-month intervals. I advise every patient with this diagnosis to remain permanently on the medication at the same doses that relieved the symptoms, at the risk of symptom recurrence if they choose to discontinue their treatment.
Patients who present with clear cut symptoms of either euphoric or dysphoric hypomania, or who have a history of uncontrollable rage or violent outbursts are started on a mood stabilizer. If necessary, an antidepressant drug can be added later after the mood has been stabilized.
As previously mentioned, patients with mixed or rapid cycling states, as well as those requiring detoxification from addictive anti-anxiety drugs are treated in a hospital setting. They usually respond to combination therapy with mood stabilizers and antidepressants.
Patients with co morbid borderline personality disorder require combination therapy with a mood stabilizer, an antidepressant and an atypical anti-psychotic drug (Risperdal, Zyprexa, Seroquel, Geodon). Once they have achieved mood stability, psychotherapy, which is usually necessary, has a good chance of being effective. The outcome is good with long-term psychotherapy and permanent maintenance medication monitoring.
Patients with co morbid ADHD are treated with a mood stabilizer and an older tricyclic antidepressant such as desipramine or nortriptyline. If this combination proves unsuccessful, they may be tried on a mood stabilizer combined with a stimulant such as Ritalin, Dexidrene, Adderall, Provigil, or Concerta.
Patients with co morbid alcohol or substance abuse, who are able to remain substance-free long enough to enable adequate mood stabilization, often find their craving for substances disappears or diminishes considerably. More than 50% of these patients are able to remain off drugs or alcohol. This compares to the 10% of true recoveries reported by Alcoholics Anonymous for primary alcoholism.
Patients with co morbid personality disorders do well initially so long as they are motivated to please the treater (authority figure). When they become defiant and act rebellious, they usually undermine their treatment. Long term prognosis for this group of patients is generally poor.
Patients with co morbid medical conditions tend to remain well stabilized as long as their medical conditions are under good control. Any metabolic disruption such as fever, infection, uncontrolled diabetes, uncontrolled thyroid states, pain syndromes requiring narcotic pain killers, etc. can interfere with adequate mood stabilizing medication, resulting in recurrence of mood disorder symptoms.
Finally, a word about an old standby class of medications, which are sometimes effective for patients who have failed on or cannot tolerate any of the newer antidepressant drug classes. The monoamine oxidase inhibitor antidepressants (MAOI's) were the first drugs discovered to be effective as antidepressants in the late 1950's. They went into eclipse because of dangerous hypertensive reactions that occurred in patients taking these drugs who ate certain common foods (cheese reaction) or used certain medications. It was later found that patients with atypical depression were uniquely responsive to this class of drugs if one avoided the foods and medications known to cause adverse reactions. These drugs remain a useful emergency backup for patients unable to benefit from the newer drug classes. They can be used safely if patients are educated about what foods and medications they need to avoid. MAOI drugs like Nardil, Marplan and Parnate have been very effective in controlling anxiety and depression in patients with bipolar spectrum disorder.
Psychosocial Dilemma: Suicidal Behavior Among Youngsters Treated with Antidepressants
A great deal of media attention during the past decade has centered on the occurrence of suicidal behavior among children and adolescents who have been treated with antidepressant drugs, especially the selective serotonin reuptake inhibitors. Black Box warnings now appear on the packaging inserts of most of these drugs and many physicians have become wary of treating depressed youngsters with antidepressants. In addition, several of the perpetrators in the rash of school shootings that have rocked our nation had been or were being treated with one or another of these drugs at the time of their violent crimes. These unfortunate events focused the glare of publicity on treatment issues in child and adolescent psychiatry. Where the problem really lies, I suspect, is with issues of diagnosis. However, this aspect has received scant if any public attention.
Ever since the advent of the SSRI's , treaters have encountered an occasional patient who developed intense suicidal pre-occupation shortly after starting an SSRI. This usually resolved quickly after stopping or changing the medication. Patients who experienced this phenomenon rarely went on to actual suicidal behavior. What appeared to be happening here was that the drug induced sudden and intense obsessional ideation - a clue that we might have unmasked a bipolar spectrum disorder. Child and adolescent psychiatrists are starting to recognize that a significant number of their depressed patients, especially those demonstrating symptoms of anger / agitation / irritability, may actually fit into the soft bipolar spectrum. Multi-site research studies carried out by collaborating members of The Spectrum Project, an international consortium of academic researchers, suggest that more than half of all patients diagnosed with unipolar depression will eventually develop bipolar symptoms. Treatment with antidepressants may fail with these patients, or it may precipitate the rapid onset of bipolar symptoms. The occurrence of the latter could account for the suicidal behavior and/or the murderous rage evidenced by the troubled youngsters mentioned earlier.
Clearly, we must continuously strive to refine our diagnostic skills, to search for objective diagnostic parameters and to educate our trainees to recognize the nuances of clinical diagnoses that lie outside the confines of the official psychiatric nomenclature. At the time of my retirement from active practice in early 2005, only a few academic psychiatry training programs in the United States were teaching their residents about the soft bipolar spectrum. Since effective pharmacotherapy is contingent upon accurate diagnosis, prior educational deficiencies must be targeted and corrected by informed continuing education programs for physicians.
http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-publication.shtml
http://www.blackdoginstitute.org.au/public/bipolardisorder/bipolardisorderexplained/index.cfm
http://www.fpnotebook.com/Psych/Bipolar/BplrDsrdr.htm
http://en.wikipedia.org/wiki/Bipolar_disorder
http://www3.interscience.wiley.com/journal/118516344/home
http://www.helpguide.org/mental/bipolar_disorder_symptoms_treatment.htm
International Society for Bipolar Disorders
Evaluation for Depression
http://www.med.nyu.edu/psych/screens/depres.html
http://www.oqp.med.va.gov/cpg/MDD/MDD_cpg/content/appendices/mdd_app1_fr.htm
http://www.fpnotebook.com/Psych/Depression/MjrDprsnDfrntlDgns.htm
http://www.swin.edu.au/victims/resources/assessment/affect/bdi.html
How to chart your moods
http://www.manicdepressive.org/moodinstruct.html
http://www.manicdepressive.org/images/moodchart.pdf
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Dr. A Prabhu Dessai Consultant Psychiatrist
Panaji , Goa 403001
India
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