When was manic depression first discovered

Here's a look at what…. Health Conditions Discover Plan Connect. The History of Bipolar Disorder. Medically reviewed by Timothy J. Legg, Ph. Ancient beginnings 17th century studies 19th and 20th century Bipolar disorder today Introduction Bipolar disorder is one of the most highly investigated neurological disorders.

Ancient beginnings. Studies of bipolar disorder in the 17th century. Bipolar disorder today. Read this next. Is Bipolar Disorder Hereditary? Risk Factors for Bipolar Disorder. Medically reviewed by N.

Bipolar Disorder vs. Obtaining the right diagnosis for bipolar disorder can be difficult, particularly because the symptoms often mimic those of other types of bipolar disorder, or even different mental health conditions, such as depression or schizophrenia.

Get help for bipolar disorder at Alvarado Parkway Institute. Alvarado Parkway Institute has been providing mental health services to the people of San Diego for over 35 years. Call our hour crisis line today at Modern definitions of bipolar disorder According to NAMI, there are four different types of bipolar disorder defined in the latest version of the DSM: Bipolar I disorder People with bipolar I disorder experience manic episodes that last for at least seven days or are so severe that they require hospitalization.

Bipolar II disorder Bipolar II disorder is characterized by a pattern of interspersed manic and depressive episodes, but the symptoms are often much less severe than those of bipolar I disorder.

Although the action mechanism underlying this synergistic effect has not been elucidated, a reinforcement of serotonergic neurotransmission has been hypothesized. In this sense, lithium causes a presynaptic increase in serotonergic function, due to an increase in the reuptake of tryptophan for its conversion into serotonin [ 46 ].

Finally, in the late s, many articles assessing the effectiveness of lithium in various mental disorders were published. These covered schizophrenia, substance abuse including alcoholism , aggressive or impulsive abnormal behaviours, premenstrual syndrome, and so forth.

Results, unfortunately, were rather poor. This means that, for the first time in history, the rational pharmacotherapeutic treatment of mental disorders took place, a process that would be completed with the clinical introduction of chlorpromazine, imipramine and benzodiazepines in the following years [ 24 , 97 , 98 , 99 , ]. But despite these great contributions, lithium is a clear example how an effective drug was unable, in an unwelcoming environment, to find its therapeutic gap.

Beverly S. Burton in the USA was the first person who synthesized valproic acid in [ , ]. Valproic acid is 2-propylvaleric acid or N -dipropylacetic acid.

It is a simple branched chain octacarbon aliphatic molecule [ , ]. It was not thought to be clinically useful because of its poor solubility in water but good solubility in fat [ ]. It was only used as an organic solvent at that time. During World War II, German scientists tried to find substitutes for butter [ ] and rediscovered the synthesis of valproate. After WWII, valproic acid became a popular organic solvent in various industries in Western countries.

It was commonly used as a diluent to solubilize other drugs [ ]. In , George Carraz and his colleagues working at the Laboratoire Berthier in Grenoble, France, studied the anticonvulsant activity [ ] of various khellin compounds [ ]. They used valproic acid as a diluent to dissolve the khellins. The results of their study showed that a correlation between anticonvulsant activity and different doses of the tested compound cannot be established but that the diluent has the anticonvulsant activity instead of the khellin derivatives using the pentylenetetrazol convulsion model [ , ].

The investigators realized that all of the solutions contain valproic acid [ , , , ]. Therefore, it has to be the effective anticonvulsant, describing an excellent story of pure serendipity [ ]. The investigators believed why the concentration of amine compounds such as imipramine or desipramine are higher in the brain because those drugs have an —N— CH 3 2 or —NH—CH 3 group, having an obvious lipid solubility. Those drugs can cross the blood-brain barrier easily, resulting in having higher concentration in the brain [ ].

They conducted a series of clinical drug trials in epileptic patients [ , , ]. Borselli and Lambert found that valpromide works as a sedative, particularly when used with other existing anticonvulsants such as phenobarbitone [ ]. They also observed that valpromide and valproate have anticonvulsant [ ] and psychotropic effects even when administered alone. The first report of mood-stabilizing effects of valproate in patients with bipolar disorders appeared in in the French literature [ ].

Besides the French study on the psychotropic benefit of valpromide, Hinderk M. Pierre A. Lambert, French psychiatrist, a pioneer in the field of psychopharmacology. His role in the conceptualization of mood stabilizers gained great importance in the early stages of the psychopharmacological era. Valproate was first introduced as an antiepileptic drug in France in It has been used in the Netherlands and Germany since , as well as in the United Kingdom since It became available in the USA in [ ].

The manufacturer, Laboratorie Berthier, had long stopped producing and promoting valpromide as sodium valproate. But it has been sold well in France and abroad [ ]. They were interested in pursuing its antimanic effect.

They supported a landmark multicentred, randomized, double-blind, placebo-controlled, parallel group drug trial [ ]. This study included acutely manic hospitalized patients meeting for the diagnosis of manic disorder of the Research Diagnostic Criteria [ ]. Being considered as one of the most stringent clinical drug trials with the largest number of patients with bipolar disorders in history, the main results of the study showed that divalproex and lithium are more effective than placebo to reduce the symptoms of acute mania and that divalproex is as good as lithium as an antimanic treatment [ ].

In , the FDA approved divalproex sodium for its antimanic effects Table 2 based on the results of this study and other studies [ , ].

The study by Bowden et al. At that time, divalproex sodium was a major psychiatric product in the USA due to its extensive commercial promotion.

Divalproex sodium was often featured besides the AADs such as risperidone or olanzapine in symposia sponsored by industry and in supplementary issues of professional journals. From to , the number of divalproex sodium prescriptions was soared in the USA, whereas that of lithium was declined [ ]. For example, By contrast, the number of prescription of lithium was decreased year by year [ ].

Both valproic acid and lithium have gained popularity in Latin-American countries. Heenren et al. Like lithium, valproate has been approved as an add-on to increase anti-manic efficacy with olanzapine and risperidone in , quetiapine in , as well as aripiprazole in Table 2. At the same time, valproate has also been found to have problematic side effects such as gastrointestinal effects, tremor, sedation, pancreatitis, liver toxicity, weight gain and polycystic ovarian syndrome.

Although some treatment guidelines for bipolar disorder suggest that valproate should be avoided during pregnancy due to its teratogenic risk British Association for Psychopharmacology Guidelines , others, such as the World Federation of Societies of Biological Psychiatry Guidelines recommends close monitoring and risk evaluation in every case.

However, in relation to teratogenicity, especially in unplanned pregnancy and with other adverse effects of valproate, such as the risk polycystic ovary syndrome, the benefits should be highlighted often outweigh the risks as patients may over-estimate the risk.

Apart from more choice from AADs, valproate prescription has also been hurt by the findings that valproate has proven not to be as good as lithium in anti-suicidal efficacy [ ] and maintenance therapy in preventing relapse [ ].

Thus, the number of prescription was declined in the decades of s and s compared to s in any country in the world where AADs were available.

Carbamazepine, a tricyclic anticonvulsant compound, was developed in the late s in the laboratories of J. Geigy, in Basel, Switzerland [ ]. In , Walter Schindler described its synthesis.

In , W. Theobad and H. Kunz reported its antiepileptic properties. This led to the use of other agents to treat manic-depressive disorders in Japan [ ]. This trend was opposite to what happened elsewhere in the world [ ]. In addition, psychiatry was neuropsychiatrically oriented and psychiatrists instead of neurologists treated most patients in Japan [ , ]. The sedative properties of carbamazepine Figure 15 led to its use for manic patients instead of other sedatives such as the barbiturates.

In the valpromide story for treating manic patients [ ], carbamazepine was applied conditions by Japanese psychiatrists exclusively to patients with epileptic or manic [ ]. Takezaki and Hanaoka [ ] in Tottori, Japan reported their first clinical series of drug trials for manic-depressive patients with carbamazepine. They reported their results in a Japanese journal in [ ].

It stated that carbamazepine has similar efficacy compared to chlorpromazine, which was discovered in [ , ]. The major criticism of the article [ ] was that there was no real evidence of efficacy of carbamazepine at all. The reason this research report was not accepted was that a mg dose of chlorpromazine was thought to be indistinguishable from placebo at a time when Western psychiatrists were using antipsychotic mega-doses [ , ].

The results of the antimanic efficacy of carbamazepine and lithium are comparable [ , ]. By the time it became more widely used, it was clear that carbamazepine had imported psychotropic properties. Carbamazepine was used in Japan for a wide range of mental conditions Figure It was useful in stabilizing aggressive outbursts in young men [ ].

Later, the use of carbamazepine for the management of episodic dyscontrol syndrome [ , ] was described in the Western literature [ ]. Carbamazapine has been observed to induce blood dyscrasias delayed its use in North America [ ], even though this serious adverse side effect was rare. USA FDA approved carbamazepine as an antiepileptic agent for adults in and for children older than 6 years of age in The FDA allowed its use for all without any age limitations in In Latin-America, there is a high degree of polypharmacy in the treatment of bipolar disorder, with anticonvulsants being the most commonly prescribed medication.

Among anticonvulsants, valproic acid was the most popular, followed by clonazepam and then carbamazepine [ ]. Oxcarbazepine has a chemical structure with a keto group instead of a double-bond between two carbons in the central ring of carbamazepine.

Those structures have also been shown to have antimanic efficacy in Europe [ ]. Oxcarbazepine has a favourable side effect profile producing less blood dyscrasias and less drug-drug interactions. To date, the pharmaceutical industry is not interested in developing carbamazepine or oxcarbazepine for treating other phases of bipolar disorder. Despite the progress accomplished, treating bipolar disorder with lithium, valproate and carbamazepine involves four major loopholes:.

Good number of patients present themselves with tolerability problems, due to the frequent adverse effects of those drugs. The depressive phase still constitutes a serious problem, since lithium, carbamazepine and valproate are more effective in relieving symptoms in the manic than the depressive phase.

Rapid cycling and mixed mania dysphoric respond poorly to treatment, etc. Although carbamazepine was already used in Europe as a substitute for lithium or in combination in resistant cases, the commercial success of valproate was the ultimate reason that stimulated the evaluation of the new anticonvulsant agents in treating bipolar disorders, particularly when it has been demonstrated in the field of epilepsy that they entailed better profile of side effects, interactions, toxicity and teratogenicity [ ].

With those premises and significant financial support from the pharmaceutical industry, those new antiepileptics are aimed to displace lithium and second-generation anticonvulsants in treating bipolar disorder, a pathology at the entrance door to the emerging juicy market of psychiatric disorders. In the individual analysis of the use of these new antiepileptic drugs in bipolar disorder, lamotrigine has been the most contrasted agent, both from the clinical and safety perspectives [ , ].

Lamotrigine has been licensed for the indication in preventing relapse of having future depressive episodes in patients with bipolar disorder. Lamotrigine was the third of the so-called new generation of antiepileptics to be marketed, after vigabatrin and felbamate.

But those last two drugs were not studied as mood stabilizers because after their commercialization as antiepileptic drugs, significant idiosyncratic side effects were discovered, such as visual field loss or aplastic anaemia, limiting their use to special cases of epilepsy Lennox-Gastaut syndrome, for example. In the case of lamotrigine, its side effects profile is more favourable in general than that of classic antiepileptic drugs, despite the feared of infrequent Stevens-Johnson syndrome.

Lamotrigine is a phenyltriazine that was synthesized in the early s at Wellcome Research Laboratories Beckenham, Kent, England as part of a program to develop new antiepileptic agents that could be better tolerated than those available at that time [ ].

This program was based on the mids hypothesis that folates had proconvulsant properties, so that antiepileptics were thought to exert folic acid antagonistic effects [ ].

Taking pyrimethamine as a reference, a substance developed in as antimalarial for the treatment and prevention of malaria , a series of structurally analogous phenyltriazines were synthesized to improve its anticonvulsant activity. One of these compounds, BWU, presented a good anticonvulsant activity but a low antifolate activity, which they tried to optimize.

As a result, lamotrigine was obtained, a compound with great anticonvulsant activity but weak dihydrofolate reductase inhibitory power [ ]. Phase I clinical trials started soon, showing excellent pharmacological properties. Lamotrigine was finally approved in in Ireland for use in epilepsy.

Similarly, in those initial studies, Smith et al. The first author who produced scientific data on the efficacy of lamotrigine in bipolar disorder was Richard H. Having attended several international conferences, Weisler knew this molecule before it was approved in the USA and anticipated its possible use in psychiatry.

After importing the drug from Europe and requesting authorization from the FDA for compassionate use in , Weisler used lamotrigine to treat two long-term bipolar patients—a year-old white male patient with bipolar II disorder and rapid cycling, as well as a year-old female patient with bipolar I mood disorder with predominance of major depressive episodes and several suicide attempts.

At that time, those two patients were refractory to all available pharmacological treatments—lithium, carbamazepine, clonazepam, valproate, 11 different antidepressants including some of those only being available in Europe then , buspirone, levothyroxine and verapamil.

The treatment regimen included, in addition to lamotrigine, other pharmacological agents such as lithium carbonate, bupropion and levothyroxine, in one case and only levothyroxine, in the other case. Both patients showed an evidence of clinical improvement after several weeks, a rapid normalization of social and family relationships and one of them even resumed working activities. In , after the presentation of those clinical cases, the company marketing lamotrigine, Burroughs Wellcome, brought together in its research facilities in Beckenham England a series of international experts in bipolar disorder to address the possibility of developing of a research program on lamotrigine to treat this psychiatric disorder.

Initially, they agreed to start an open, multi-centre clinical trial five international centres with a sample of 75 patients in any active phase of the disorder, either type I or type II and a follow-up of 12 months, treated with lamotrigine in monotherapy or in combination treatment. Secondary analyses have shown additional benefits in other aspects related to the depressive episode and good tolerability with the most common adverse effects being dizziness, tremors, drowsiness, headaches, nausea and rash [ ].

Given the positive results of this open study, GlaxoSmithKline launched between and an ambitious program of a controlled double-blind phase III trials and enrolled patients from four continents—5 trials in acute episode of bipolar depression, 2 in acute episode of mania, 2 in the prevention of manic or depressive episode and 2 in rapid cycling patients [ ].

Unlike typical antipsychotics being more effective in the control of mania than depression, lamotrigine is especially effective in patients with a predominance of depressive phases. Similar results were obtained in the other four trials.

These poor results might be due to the need to slowly increase the dose of lamotrigine up to 10 weeks to reach the final dose to avoid the appearance of rash [ ]. Subsequently, a meta-analysis considering all trials would confirm a significant, albeit small, efficacy of the treatment with lamotrigine [ ]. By contrast, in double-blind clinical trials with patients in the manic phase, lamotrigine 50 mg yielded negative results [ ], presenting no statistical differences with placebo and lower efficacy than lithium.

But in those studies, the risk of shift from mania to depression is not more than to placebo. Yet, the best results with lamotrigine were obtained in studies of relapse prophylaxis in patients with bipolar disorder shown in two randomized double-blind trials which compared the efficacy of lamotrigine with that of lithium and placebo over 18 months. The combination of data from both trials also showed that lamotrigine is effective in the prevention of mania, although the results is not as robust as that with lithium [ ].

These findings confirmed the characteristically antidepressant profile of lamotrigine as a mood stabilizer, as opposed to other drugs available at the time and obtained its approval by USA FDA in Table 2. In addition, they suggested the possibility to combine lamotrigine with lithium to obtain more symmetrical results in relapse prevention [ ]. The effectiveness of lamotrigine in rapid cycling patients was also suggested, although data were based on a placebo-controlled clinical trial, is only positive in bipolar type 2 [ ].

Finally, it was also confirmed that the combination of lithium and lamotrigine is safe and useful in refractory bipolar depression [ , ] and that the combination with valproate or carbamazepine is also possible, although implying more interaction risks [ ]. Gabapentin was one of the first third-generation antiepileptic drugs to be studied for bipolar disorder and as almost all of them, it was initially evaluated for the treatment of mania.

Although most open studies have positive outcomes [ ] but the two controlled clinical trials produce negative results [ , ] and raised considerable doubts about its efficacy. In the first one [ ], lamotrigine shows better outcomes than gabapentin. In the second one, surprisingly, placebo is better than gabapentin in manic patients treated with lithium [ ]. However, gabapentin could be an interesting drug as an enhancer of other mood stabilizers in cases in patient with a high anxiety component [ ].

This is especially relevant at present, since many authors advocate combined treatment to prevent the natural disease progression towards a shortening of remission periods [ ].

The history of topiramate shows paradigmatically how research on potentially anticonvulsant drugs is evolving. Topiramate was discovered in by Bruce E. Maryanoff and Joseph F. It was initially synthesized as a hypoglycaemic agent. In fact, topiramate is a sugar, a derivative from fructose. After having known its potential efficacy in diabetes being limited, the investigators studied topiramate in various animal models of different diseases, proving its anticonvulsant efficacy in rats.

The preclinical research showed that the presumed antidiabetic was a potent antiepileptic. Some open studies suggested that it could be an effective drug as an add-on therapy in bipolar patients with partial response to other drugs [ ] and a monotherapy [ ]. But placebo-controlled clinical trials in manic patients cannot prove its efficacy [ ], despite that several controlled trials of high methodological quality were carried out. As for tiagabine, little relevant data exist to show its effect in bipolar disorder, although a study conducted in the Stanley Foundation Bipolar Network indicated that its mood stabilizing potential is scarce or null, together with a certain risk of seizure induction [ ].

As mentioned before, oxcarbazepine, a keta analogue of carbamazepine, was developed in the s as an improved alternative to carbamazepine. In addition to the initial studies from the s, recent data exist from experiments using oxcarbazepine to treat bipolar patients. Case series with positive results have been reported [ ]. In addition, an open study with 12 patients receiving oxcarbazepine has been published, showing good results in participants with mild or moderate forms of mania, worsening in symptoms after discontinuing the drug and becoming improved again after resuming treatment [ ].

In any case, the APA advises the use of oxcarbazepine as a reasonable option in treating bipolar patients who do not respond to established treatments but more clinical trials are needed to confirm its potential as mood stabilizer in the maintenance treatment.

Licarbazepine, an active metabolite of oxcarbazepine, was also evaluated in controlled clinical trials for manic episodes in bipolar disorder patients, with unsatisfactory results [ ]. With respect to levetiracetam, pregabalin, retigabine, or zonisamide, the data published from patients with bipolar disorder are limited, although their properties are being assessed as mood stabilizers.

The delay in the action onset of classical mood stabilizers in the treatment of symptomatic acute manic symptoms enabled the study with the use of antipsychotic drugs in this disorder [ ].

Chlorpromazine was the only traditional antipsychotic drug or first-generation antipsychotic drug, FGA approved by USA FDA in for the treatment of manic episodes in bipolar disorder. Several clinical trials contrasted the efficacy of chlorpromazine in acute mania, both in monotherapy [ 83 , ] and in combined treatment with lithium salts [ ]. Nevertheless, its use in bipolar disorder was limited due to its poor tolerability, causing sedation and hypotension and the advent of new atypical antipsychotic drugs AADs, or second-generation antipsychotic drugs, SGAs.

The clinical introduction of risperidone on the USA market in to treat patients with schizophrenia heralds the advent of AADs and the clinical introduction of those agents reinvigorated the interest in therapeutic research on the different phases of bipolar disease [ ]. Besides, the unique biochemical properties of AADs clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine and cariprazine , mainly their ability to antagonize dopamine receptors, together with other peculiarities of their pharmacological receptor profile and their effects on multiple neurotransmission systems [ ] also fostered their study as potential antimanic agents [ ].

In addition to dopamine D 2 antagonist effects, AADs block 5-HT 2 serotonergic receptors, basically 5-HT 2A and 5-HT 2C and some of them, such as aripiprazole, ziprasidone and asenapine, are 5-HT 1A receptor partial agonists [ ], which could result in an enhancement of noradrenergic and dopaminergic neurotransmission [ ].

Although the exact mechanisms of AADs in the treatment of mania remain unclear, it seems obvious that this type of drugs have a specific antimanic effect regardless of the presence of comorbid psychosis or the degree of sedation induced by the agents [ 2 ]. Olanzapine was the first atypical antipsychotic drug to have been licensed for the indication of treating acute mania.

The first of those was a placebo-controlled trial [ ] with a three-week follow-up period. The study results showed a mean reduction in the YMRS score of The mean modal dose of olanzapine Subsequent studies confirmed the efficacy of olanzapine in acute mania, with an efficacy superior to valproate and lithium [ ]. In any case, the antimanic efficacy of AADs was later revealed by a series of randomized, placebo-controlled studies [ 12 , , , , , ], suggesting that all AADs, as a pharmaceutic group, have a class-effect in treating mania.

Almost all AADs got approval to treat mania one by one—risperidone in ; quetiapine, ziprasidone and aripiprazole in ; asenapine in ; as well as cariprazine in were approved by the USA FDA as monotherapic agents for the antimanic indication Table 2. In addition, some of them were also approved for the prevention of relapse in patients with bipolar disorder who in a manic episode had already responded to the treatment with those antipsychotics Table 2.

At present, AADs are the first line of treatment for the manic phases of bipolar disorder [ ]. Various AADs expanded their indications to treat all three clinical phases of bipolar disorder. Seemingly most AADs, if not all, can get the indication for relapse prevention if they are combined with the use of lithium or valproate Table 2. Finally, olanzapine always in combination with fluoxetine in , quetiapine in and lurasidone in have been approved for the treatment of depressive episodes in bipolar disorder.

This may be the reason why, recently, the number of scientific publications on bipolar disorder [ 9 ] and AADs have suddenly and exponentially increased in some countries of Asia and Europe and in Australia [ , , , , ]. The treatment of bipolar depression is more complex than the treatment of manic episodes. It requires different therapeutic approaches from unipolar depression [ ].

Also, the scientific evidence on the role of AADs is smaller and, in some cases, the results of meta-analyses have given rise to inconsistent conclusions [ ]. The antidepressant properties of some AADs could be due to their ability to modulate three monoaminergic systems noradrenergic, serotoninergic and dopaminergic involved in the pathophysiology of depression [ ]. In the case of quetiapine, its active metabolite norquetiapine helps serotonergic transmission, acting as a partial agonist of 5-HT 1A receptors, in addition to working as a potent inhibitor of the noradrenaline transporter, which increases noradrenergic functionality [ , ].

Although olanzapine is approved by USA FDA in the treatment of bipolar depression, that is the case only in combination therapy with fluoxetine. The BOLDER studies, placebo-controlled and 8 weeks long, confirmed that quetiapine at daily doses of — mg is superior to placebo in the total reduction of depressive symptoms according to the Montgomery-Asberg Depression Rating Scale. MADRS and that the improvement occurred from the first week in all the main symptoms of depression.

Likewise, quality of life and anxiety are improved to a greater extent with quetiapine and this improvement was independent of the presence or absence of sedation [ , ]. With respect to EMBOLDEN trials, an assessment was performed at week 8 and patients who met specific response criteria entered a week treatment extension phase. In addition, paroxetine does not differ from placebo [ ]. In those studies, in acute episodes of bipolar depression, quetiapine achieves higher and earlier response and remission rates than placebo and it does so from the first or second week.

This decision to pursue clinical drug trial of lurasidone for patients with depressive episode in bipolar disorder was influenced by three relevant factors [ ] because lurasidone has:. Lurasidone is the first AAD whose efficacy in bipolar disorder was studied in the treatment of the depressive phase exclusively. The investigators observed that in patients treated with lurasidone for six weeks, the mean MADRS score is decreased more than those in the control group.

Therefore, the pharmaceutical company Sunovion Pharmaceuticals, Inc. The positive results of those trials and an open six-month long-term follow-up study allowed USA FDA approval of this agent in June , for the treatment of depressive episodes of bipolar I patients. It means different things to different people APA, According to one specific definition, it is a drug that has both antimanic and antidepressant effects on both mood states [ , ]. In conservative definition, it means a drug that has therapeutic efficacy in 2 of 3 different mental states, as shown in Table 2 [ ].

According to this broad definition, tricyclic antidepressants do not belong to this category to treat patients with bipolar disorders. The results of meta-analysis data from clinical trials has shown that the rates of mania induced by tricyclics, SSRIs and placebo are Venlafaxine and paroxetine have been found to have beneficial psychotropic properties.

Valproic acid and carbamazepine have never been identified to switch the mood of bipolar patients from a depressive to a manic phase. In this paper, we have used the USA FDA approval status as the milestone for describing drugs for the treatment of bipolar disorders.

Since , olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine and cariprazine have been approved for antimanic indication.

Currently the AAD market is saturated with antimanic agents as listed in Table 2. No more motivation exists for a pharmaceutical company to invest money to develop oxcarbazepine or another antiepileptics for an antimanic indication. Hence, those drugs are most likely to remain off-label use for antimanic effects. No shortage of available antimanic agents is shown on the market Table 2. But lamotrigine or similar drugs, rather than valproic acid or carbamazepine, continues to draw attention in the treatment of patients with bipolar disorders.

Their rare characteristic is their efficacy for both poles of bipolar depression. The direct and delayed consequences of the introduction of the first psychotropic drugs in the s have been multiple and lithium salts played a fundamental role [ 30 , 63 , 97 , , ].

Clinical research methodology also benefited from the appearance of those drugs, specially lithium salts, with the rise of multicentre, double-blind, cross-over, randomized clinical trials, etc. Lithium played a decisive role in this whole process [ 62 ].

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